Introduction

Front. Immunol.

Frontiers in Immunology

Front. Immunol.

1664-3224

Frontiers Media S.A.

10.3389/fimmu.2023.1127277

Immunology

Review

The transient receptor potential channels in rheumatoid arthritis: Need to pay more attention

Niu

Mengwen

¹ Zhao

Feng

¹ Chen

Rui

² Li

Ping

¹ ^* Bi

Liqi

¹ ^*

¹ Department of Rheumatology and Immunology, China-Japan Union Hospital of Jilin University, Changchun, China ² Department of Cardiology, China-Japan Union Hospital of Jilin University, Changchun, China

Edited by: Ping-Heng Tan, Chi Mei Medical Center, Taiwan

Reviewed by: Chenhui Wang, Huazhong University of Science and Technology, China; Xin Luo, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, China

*Correspondence: Ping Li, li_ping@jlu.edu.cn; Liqi Bi, bilq@jlu.edu.cn

This article was submitted to Inflammation, a section of the journal Frontiers in Immunology

01 03 2023

2023

1127277

19 12 2022 06 02 2023

2023

Niu, Zhao, Chen, Li and Bi

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

Rheumatoid arthritis (RA) is characterized by the augment of vascular permeability, increased inflammatory cells infiltration, dysregulated immune cells activation, pannus formation and unbearable pain hyperalgesia. Ca²⁺ affect almost every aspect of cellular functions, involving cell migration, signal transduction, proliferation, and apoptosis. Transient receptor potential channels (TRPs) as a type of non-selective permeable cation channels, can regulate Ca²⁺ entry and intracellular Ca²⁺ signal in cells including immune cells and neurons. Researches have demonstrated that TRPs in the mechanisms of inflammatory diseases have achieved rapid progress, while the roles of TRPs in RA pathogenesis and pain hyperalgesia are still not well understood. To solve this problem, this review presents the evidence of TRPs on vascular endothelial cells in joint swelling, neutrophils activation and their trans-endothelial migration, as well as their bridging role in the reactive oxygen species/TRPs/Ca²⁺/peptidyl arginine deiminases networks in accelerating citrullinated proteins formation. It also points out the distinct functions of TRPs subfamilies expressed in the nervous systems of joints in cold hyperalgesia and neuro-inflammation mutually influenced inflammatory pain in RA. Thus, more attention could be paid on the impact of TRPs in RA and TRPs are useful in researches on the molecular mechanisms of anti-inflammation and analgesic therapeutic strategies.

rheumatoid arthritis transient receptor potential channels inflammation calcium signal neuro-inflammation inflammatory pain

1 Introduction

Rheumatoid arthritis (RA) is a systemic inflammatory autoimmune disease characterized by the infiltration of T cells, B cells, and inflammatory cells such as neutrophils, macrophages, and so on within joints. Inflammatory factors and autoantibodies produced and secreted by immune cells act on cartilage, tendons, ligaments, and bone tissues, causing joint swelling, pain hyperalgesia, pannus formation, and eventually bone destruction (1, 2). It has a high prevalence and disability rate, bringing a huge economic burden and pressure to society and families (3). While the pathogenesis of RA remains unclear, so, it is still a long way to go.

Ca²⁺ affect almost every aspect of cellular functions, involving cell proliferation, apoptosis, migration as well as signal transduction. Calcium ion as a necessary molecule of physiological signal transduction in eukaryotes, it functioned as a central manipulator of inflammation as well as immune response in RA (4). As non-selective Ca²⁺ permeable channels, TRPs expressed on neutrophils (5, 6), chondrocytes (7, 8), fibroblast-like cells (FLS) (9) and nervous system (10, 11) have been proven to regulate cation flow and potential changes, helping them participate in RA.

The TRP channel superfamily consist of 28 members (27 in humans) in mammals (3). Based on sequence homology, the superfamily is divided into seven subfamilies in mammals (12). Four subfamilies of TRPs have been well studied which are known as TRPCs, TRPVs, TRPMs, and TRPA1. There are also different categories within each subtype, including the Canonical subfamily (TRPC1-7), the Vanilloid subfamily (TRPV1-6), the Melastatin subfamily (TRPM1-8) (13, 14). As they can be activated by diverse stimuli no matter in extracellular and intracellular circumstances, for example the alteration of the temperature, osmolarity, depletion of calcium stores, as well as cytokines. Therefore, they play a series of important roles in physiological and pathological status (15–17).

Though TRPs have been studied in many other diseases such as cardiovascular, renal, tumor, lung inflammation and other inflammatory diseases, researches on their roles in rheumatoid arthritis are limited. We carefully selected representative articles and explore the different and indispensable roles of these TRPs in RA pathogenesis and in cold and inflammatory stimuli perceptions as well as their influence on neuro-inflammatory interaction outcomes. At the same time, we also show our ideas as we illustrate the relevant issues.

2 Role of TRPs in vascular permeability

RA patients typically complain of swelling and stiffness of joints. Vascular endothelial cells (ECs) are involved in immune and inflammatory responses because they can produce different cytokines and react with immune-inflammatory factors, causing the augmentation of endothelial permeability (18). The increase of Ca²⁺ in ECs closely related to endothelial cell permeability (19). However, the exact molecular mechanism involved in the increase of endothelial permeability is not yet completely known.

2.1 TRPs promote the Ca<sup>2+</sup> influx of ECs

The inner layer of blood vessels consists of adjacent ECs and their tight connections. The integrity of the endothelial layer was guaranteed by intercellular linkages comprising of adherents and tight junctions (20, 21). The calcium influxes/transients cause adherents junction disassembly, cytoskeletal rearrangements and facilitate ECs retraction. Therefore, the morphology of ECs was transformed to a round shape, and gaps between them were augmented, inducing their permeability increase (21, 22). The concentration of intracellular calcium ion promoted with the increased opening of TRPC1 on ECs, which accelerated the formation of actin stress fibers and enhanced the stretching and deforming ability of ECs, thus leading to increased permeability (19). The TRPC6 expressed in ECs collaborated with platelet/endothelial cell adhesion molecule-1 (PECAM) to surround leukocytes during their trans-endothelial migration (TEM) and could help them in their migration. The down-regulated expression of TRPC6 or shRNA knockdown in ECs arrested neutrophils over the junction, similar to when PECAM was blocked (23).

Among the 28 identified and widespread mammalian TRP channel isoforms, at least 19 are expressed in ECs (24, 25), and the transient receptor potential canonical channels (TRPCs) are the subfamily of TRPs closely related to endothelial cell permeability. ECs express six non-selectively cation permeable TRPCs, which are TRPC1, TRPC3, TRPC4, TRPC5, TRPC6, and TRPC7 (25, 26). Most studies agreed that the influx of Ca²⁺ into ECs through TRPC1, TRPC4, and TRPC5 was mediated by the store-operated Ca²⁺ entry (SOCE), starting with the depletion of Ca²⁺ in endoplasmic reticulum (ER) stores (27, 28). But, some studies had questioned whether the TRPC1/4/5 channels mediated the increase of Ca²⁺ through SOCE (29). It has been reached an agreement that the influx of Ca²⁺ through TRPC3, TRPC6 and TRPC7 was induced by the receptor-operated Ca²⁺ entry (ROCE). An important stimulant of TRPCs is the α-subunits of G-proteins. Thus, inflammatory stimuli cause the activation of G-protein-coupled receptors (GPCR) and the phospholipase C (PLC) promote the opening of TRPC channels (30, 31). Even though TRPCs may also activated by some other stimulates, the mainly same effect is the increase of calcium influx in ECs. The mechanisms of different TRPC subfamilies in mediating calcium ions entering into endothelial cells are shown in Figure 1 .

Figure 1

Diagram of TRPs-mediated Ca²⁺ entering into endothelial cells and neutrophils chemotaxis and adhesion in inflammation. Diagram of TRPs-mediated Ca²⁺ entering into endothelial cells and neutrophils chemotaxis and adhesion in inflammation. Inflammatory stimuli (such as TNF-α, ROS, VEGF) influence the expression and activation of TRPs expressed on ECs. Activation of specific GPCRs on the cell surface causes the activation of PLC which cleaves the membrane phospholipid PIP2 into inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). DAG induce the activation of TRPC3, TRPC6, and TRPC7 channels, and the way of the influx of Ca²⁺ called receptor operated Ca²⁺ entry (ROCE). IP3 binds to IP3 receptors (IP3Rs) present on the ER, causing Ca²⁺ release from intracellular stores. Then the Ca²⁺ sensor stromal interaction molecule1(STIM1) proteins gather to the membrane of ER and activate the channels of orai1 and TRPC1/4/5, thus promoting extracellular Ca²⁺ influx which is called as SOCE. TRPCs also mediate the adhesion of neutrophils through regulating the anchor link of neutrophil and epithelial cells. TRPC6 expressed in endothelial cells colocalize with PECAM, surrounding leukocytes and promoting neutrophil trans-endothelial migration.

2.2 The activation of TRPs by inflammatory factors

Inflammatory factors interact with TRPs on vascular ECs of the inflammatory sites, leading to increased vascular permeability. TNF-α works as a major inflammatory factor in RA, it is often used as an inflammatory mediator to simulate the inflammatory reaction process of RA (32–35). TNF-α could cause the TRPC1 expression which medicated increased Ca²⁺ entry through SOCE, representing an important mechanism of endothelial injury through TRPC1 (19, 36). Ca²⁺ flowing through TRPC1 can also increase TRPC1 expression through positive feedback. Protease-activated receptor-1(PAR-1) activation elicited cellular responses including NF-κB activation and increased Ca²⁺ influx through TRPC1. Ca²⁺ then regulated the expression of TRPC1 expression which may be a vicious circle resulting in vascular permeability (36–38). Besides, inflammatory mediators, such as thrombin were reported to be increased in RA (39, 40). Thrombin induced the phosphorylation of TRPC1 by PKCα activation, resulting in Ca²⁺ entry and the increase in permeability in confluent endothelial monolayers (41). The inflammatory factor thrombin could also promote the association between TRPC6 and phosphatase tensin homologue (PTEN) which worked as a role of the scaffold for TRPC6, enabling the expression of TRPC6 on cell surface, which made the increase of Ca²⁺ entry (42). Therefore, the increased Ca²⁺ entry through TRPC1/6 plays an important role in augmenting endothelial permeability in RA.

Reactive oxygen species (ROS) are cellular metabolites that contain at least one oxygen atom and one or more unpaired electrons (43). ROS could damage DNA, proteins, lipids, and many other molecules (44). Phagocytes and recruited immune cells could produce a lot of ROS in the RA synovitis microenvironment (45–47). Increased ROS caused by Oxidative stress can destroy endothelial integrity by leading to Ca²⁺ influx into ECs, and disrupt the tight junctions between them (48). TRPM2 expressed in ECs can be activated by ROS and play a role as Ca²⁺-permeable channel. The sub-lytic concentration of H₂O₂ induced an increase in ECs intracellular Ca²⁺ by stimulating Ca²⁺ entry through the TRPM2, and subsequent reduction of transendothelial resistance (49).

VEGF was first isolated and named vascular permeability factor (VPF), a potent vascular permeability-enhancing cytokine and a selective mitogen for endothelial cells (50). VEGF expression was increased in vascular endothelium and synovial tissue in RA joints and was associated with inflammation and angiogenesis (51–54). VEGF could also provoke ROS production with the participation of NOX, followed by the autophosphorylation of VEGFR2 (55). Corroborating with the above paragraph, VEGF and ROS can act as two interactive inflammatory molecules synthesized at the site of inflammation, and weaken the endothelial functions. Decrease expression of TRPC6 in human microvascular endothelial cells (HMVECs) restrained the VEGF-mediated increases in Ca²⁺ and migration of HMVECs (56). Therefore, TRPC6 is an indispensable cation channels needed in the VEGF-mediated increase of Ca²⁺ in HMVECs.

VEGFs can identify and combine with their cognate VEGF receptors, including VEGFR1, VEGFR2, and VEGFR3, as well as some co-receptors (57). VEGF medicated endothelial hyperpermeability in a phospholipase C (PLC)-IP3 pathway, which result in extracellular Ca²⁺ entry via the plasmalemma store-operated TRPC1. VEGF augmented the interaction of IP3R with TRPC1 (58). VEGF could activate a receptor-operated cation current in HMVECs, in which VEGF bound with VEGFR2 which activated heterologously co-expressed TRPC3/6 channels, such as the style of VEGFR2-TRPC3 and VEGFR2-TRPC6 on cells (59). In conclusion, we hypothesized that when VEGF binds to the corresponding VEGFR or co-receptors on ECs, it may cause the activation of TRPC channels in the form of linking the body with these receptors, which leads to the increase of intracellular calcium ions and the increase of endothelial cell permeability.

3 Role of TRPs in neutrophils’ TEM and proteins citrullination

Neutrophils are the main force of the first line of immune defense and always be recruited to sites of inflammation as soon as possible. The recruitment of neutrophils and their activation against pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs) are highly coordinated and tightly regulated processes that involve the activation of various kinds of receptors as well as many ion channels (60, 61). Fluctuations in intracellular Ca²⁺ levels are hallmarks in the above complex processes of neutrophils. Hence, TRPs, as non-selective permeable Ca²⁺ channels distributed on neutrophil, have an important role in the functions of neutrophil in RA.

3.1 The contribution of TRPs to neutrophils TEM

Leukocyte TEM is the first step of their participating in the immune response and is vital to inflammation (62–66). Neutrophils can be activated by plentiful of “neutrophil-active” chemo-attractants, which initiate the TEM process, including different kinds of chemokines and cytokines (such as CXCLs) as well as fragments of complement (65). TRPC6(-/-) neutrophils had decreased Ca²⁺ transient during initial adhesion, resulting in reduced activation of Rap1 and β2 integrins and reduced binding to ICAM-1. This suggests that the TRPC6 on neutrophils is a key functional channel protein in CXCL1’s recruitment of inflammatory cells from the bloodstream (67). The deletion of TRPC1 led to reduced migration and chemotaxis of neutrophils due to disruption of Ca²⁺ gradient homeostasis within TRPC1-/- neutrophils, resulting in more disordered migration and reduced directed migration of neutrophils (68).

A large number of activated neutrophils were found in both peripheral blood and synovial tissue from RA patients (69). Different kinds of chemokines are manifested by studies highly expressed in the serum and synovial fluid in RA, for instance, the CXC-chemokines, the CC-chemokines, and the CX3C-chemokine CX3CL1 (70–73). Intracellular Ca²⁺ flow from the extracellular space induced by CXCR2 as a chemotactic agent is affected in TRPC6(-/-) neutrophils. Deletion of TRPC6 inhibited phosphorylation of AKT and MAPK molecules, which were downstream of CXCR2 receptors, attenuated actin remodeling, and thus impeded the chemotaxis of neutrophils (74). TRPC6 could also be activated by the CXC-type G-protein-coupled chemokine receptors upon stimulation with macrophage inflammatory protein-2 (MIP-2), which was essential for the arrangement of filamentous actin of migrating neutrophils (75).

TRPM7 is a member of the subfamily TRPMs and works as not only an ion channel but also kinase activity. If the TRPM7 channel or kinase activity was blocked, the ability of human neutrophils to migrate along CXCL8 chemokine gradients was significantly reduced. Kinase activity of TRPM7 affected the Akt1/mTOR signaling pathway and regulated neutrophil migration and function (5). Recent researches showed that the expression of CD147 on neutrophils from RA patients was higher than that in healthy group (76). TRPM-7-mediated the increase of Ca²⁺ and induced chemotaxis, adhesion ability, and invasiveness of RA neutrophils response to CD147. When treated with the transient receptor potential melastatin 7 small interfering RNA(si-TRPM7), the chemotaxis and the relative adhesion rates of neutrophils were reduced significantly (6).

3.2 Role of TRPs in the formation of citrullination proteins

Once neutrophils are activated by inflammatory stimuli, their intracellular Ca²⁺ concentration will be enhanced. The calcium-dependent peptidyl arginine deiminases (PADs) will be stimulated by the increased concentration of Ca²⁺ in neutrophil. PADs convert the protein arginine residues to citrulline residues, this process is called protein citrullination (77). The autoantibodies that recognize citrulline protein antigen (ACPAs) may have been present prior to diagnosis, and studies have shown that it is a major pathogenic molecule of RA (78, 79). In the process of citrullination, the PADs are the key enzymes, therefore, it is necessary to explore the influencing factors of PADs activity. So, we consider that TRPs that can cause calcium influx may play a role in promoting the activity of PADs in neutrophil.

3.2.1 TRPCs and the activation of PADs

It has been manifested that Calcium is the primary factor in the activation of PADs enzymes, because it can motivate structural changes of PADs. PADs have five calcium-binding sites, and the enzyme active sites will be exposed when they bind to calcium ions (80). At the same time, the conformational changes are accompanied by the transition from inactive to active PADs.

It has been shown that three subtypes of TRPs are expressed in human and mouse PMNs, including TRPCs, TRPMs and TRPVs (60). Receptors on neutrophils can be activated by inflammatory stimuli, leading to the activation of PLC which cleaves the membrane phospholipid PIP₂ into inositol 1,4,5-trisphosphate (IP₃) and DAG. DAG induce the activation of TRPC6 channels, through which the Ca²⁺ entry into neutrophils (81). IP₃ binds to IP₃ receptors (IP₃Rs) present on the ER, causing Ca²⁺ release from intracellular stores. Then the Ca²⁺ sensor stromal interaction molecule 1(STIM1) proteins gather to the membrane of ER and activate the Orai1 and TRPC1, thus promoting extracellular Ca²⁺ influx neutrophils (82). Increased intracellular Ca²⁺ concentration in neutrophils promotes PADs activation, which in turn leads to the formation of citrullination proteins or neutrophil extracellular traps (NETs). We have shown evidence that TRPCs offer assistance in Ca²⁺ influx through SOCE and ROCE during the process of the recruitment and activation of neutrophils, and summarized in Figures 1 , 2 .

Figure 2

Distinct Ca²⁺ signals and downstream cellular events associated with TRPs in neutrophils. Distinct Ca²⁺ signals and downstream cellular events associated with TRPs on neutrophils in RA joints. Chemokines and immune-inflammation factors stimulate the activation of receptors on neutrophils, leading to the activation of PLC and the production of molecules downstream of it. NADPH oxidase can be activated and make an increase in ROS production. ROS leads to the increase of ADPR production, which acts as the activator of the TRPM2 channel and further promotes the entry of Ca²⁺ into cells. In addition, DAG, as the activator of TRPC6, can induce increased calcium influx through ROCE. With the addition of Ca²⁺ entering by SOCE, cytosolic Ca²⁺ level rapidly increased by the SOCE, ROCE and ROS/TRPs mechanisms. Ca²⁺ catalyzes PADs which facilitate citrullination, and even promote the formation of NETs in neutrophils.

3.2.2 TRPM2 and the activation of PADs

Interestingly, most of the stimuli that lead to an increase in the calcium concentration of neutrophils also lead to the production of ROS. ROS generation and Ca²⁺ concentration in synovial neutrophils from RA patients were increased, and proinflammatory cytokines such as GM-CSF and TNF-α enhanced ROS production in neutrophils by activating NADPH oxidase (83). Moreover, ROS-dependent NETs formation was associated with enhanced PADs activity (84, 85). In line with those described above, RA neutrophils presented increased formation of NETs with elevated ROS and Ca²⁺ concentrations, accompanied by enhanced PADs mediating citrullination (86). It seems apparent that ROS and Ca²⁺ play a mutual interaction in promoting PADs enzyme activity.

Notably, TRPM2 cationic channels play a mediating role in regulating Ca²⁺ mobilization and oxidative stress in neutrophils. They regulate calcium influx in a way that is different from the SOCE and ROCE pathways mentioned above. The activating ligand for TRPM2 is ADP-ribose (ADPR), which is increased when intracellular ROS levels are high and works with intracellular calcium to activate TRPM2 (87–89). H₂O₂ was shown to prompt ADPR generation, which acted as an activator of TRPM2. The increased calcium through TRPM2 could further induce production of the ROS (90). FcγRIIIb activated by immune complexes evoked protein kinase C (PKC) activation, which promoted NADPH-oxidase in ROS production, leading to activation of TRPM2 channels, allowing significant up-regulation of extracellular Ca²⁺ into the neutrophil (91). Compared with the control group, the concentration of intracellular free Ca²⁺ and ROS production in neutrophils were significantly increased in patients with RA. The intracellular Ca²⁺ concentrations were decreased by anti-TRPM2 therapy (92). Hence, we consider that the TRPM2 work as a bridge of inflammation or oxidative stress and calcium signal in the NADPH oxidase/ROS/TRPs/Ca²⁺/PADs pathway, as shown in Figure 2 .

4 Role of TRPs in pannus formation

Angiogenesis/neovascularization is an invasive event in the pathogenesis of RA which is characterized by synovial tissue proliferation. Osteochondral angiogenesis of RA is characterized by fibrovascular tissue expressing VEGF and increased proliferation of ECs and fibroblast-like synovial cells (FLS) (93). VEGF, a key governor of angiogenesis, can regulate angiogenesis via VEGFR2 (94). The overexpression of TRPV4 up-regulated VEGFR2 trafficking and activation, controlling ECs migration and angiogenesis (95). It was also found to induce endothelial progenitor cells (EPC) proliferation and migration, which facilitated angiogenesis and enabled the development of RA (96). TRPC3, TRPC4, and TRPC5 were essential for the formation of tubular structures and revealed an essential contribution of TRPCs to the vitro tubulogenesis of endothelial cell lines (97). TRPC6 was also a cationic channel necessary for the related pathway processes of VEGF-mediated cytoplasmic calcium increase and angiogenesis (56, 98).

Accumulating data has proved that the apoptosis rate of FLS in RA is decreased, and their proliferative and invasive properties lead to progressive destruction of cartilage and bone (99, 100). TRPC6 was found somewhat higher in RA-FLS than that in OA-FLS. TRPC6 deficiency in mice weakened the development of experimental RA and CIA models and inhibited FLS invasiveness and proliferation (101). The expression of TRPM7 was significantly increased in RA-FLS, TRPM7 may have a role in reduced FLS apoptosis because suppression of TRPM7 channels increased RA FLSs apoptosis in vitro, and this was associated with endoplasmic reticulum (ER) stress activation (102). Another study found that TRPA1 activation was associated with decreased proliferation of FLS, an effect that was substantially enhanced by TNF preincubation. The reason may be that activation of TRPA1 increased calcium flux and substantially reduced cell viability by inducing necrosis (103). As we can only retrieve a few studies on the correlation between TRPs and FLS proliferation or apoptosis at present, the assured roles of TRPs in promoting the proliferation or apoptosis of the FLS are not yet clear. We are looking forward to detailed studies in this field.

5 Role of TRPs in pain perception and neuro-immune communication

RA is a serious and persistent painful disease of the distal joints in which neurogenic components are supposed to participate in its pathology. Pain is the most common complaint of patients in the rheumatology department, and the threshold of patients for pain is often lower than that of healthy people, that is, pain hyperalgesia (104). There are a large number of sensory nerve fibers in the synovium of the joint. Located on these sensory nerve fibers, TRPs act as an important superfamily of proteins that mediate heat and mechanical pain. Recent findings regarding the role of TRPs in cold and inflammatory pain hypersensitivity spouted. The mechanisms of TRPs in temperature perception, nociception, sensitization of inflammatory stimuli, and neuro-immune communication will be stated in detail in the following sections.

5.1 Role of TRPs in cold allodynia in RA

When the weather gets cold, there are many cases where patients with RA have to visit the clinic because of unbearable joint pain. Although the mechanism of the effect of cold environment on arthritis patients is not clear, it has been shown to be one of the common precursors and aggravating factors of arthritis.

5.1.1 TRPA1 in the perception of cold and blood flow sustainment

TRPA1 on neurons can perceive the changes of thermal (< 17°C), chemical (menthol, formalin, reactive lipids, etc.), and mechanical (sting, pinch, etc.) (105). Studies established that TRPA1 acted as a cold sensor in experimental models, revealing that TRPA1 was a major sensor for noxious cold (106, 107). TRPA1 protein and mRNA were overexpressed in both peripheral and central nervous system of CFA treated mice, and TRPA1 played a vital role in the development and maintenance of cold pain hyperalgesia. However, pretreatment with TRPA1 antagonist HC-030031 inhibited the above results (108). While, as a opposite, one study argued that WT and TRPA1 KO mice had no difference in the perception of thermal pain in the inflamed claw compared with that of naive mice (109). Additionally, another study hinted that TRPA1 agonists can sensitize the noxious reflex withdrawal to heat, but not cold (110). Why do they have contradictory conclusions? The reasons may be the ways and degrees of cold stimuli and the detection methods they used, and the test time points after stimulation they set. Therefore, different investigational methods may reflect controversial results.

In one study, cold exposed CFA arthritis mice developed bilateral pain sensitivity in their knee joints, which was dependent on the cold sensor, TRPA1. Moreover, blood flow was seen to increase in the joint after cold exposure which also depended on TRPA1, and due to the vasodilatory neuropeptides, including Substance P (SP) and calcitonin gene-related peptide (CGRP) (111). Thus, TRPA1 may act to influence not only its established nociceptive actions within the joint but also blood flow via neuropeptides. Then, why TRPA1 can medicate the pain hyperalgesia and still cause increased blood flow than that of the control group after cold exposure? When the animals were at room temperature, blood flow of CFA-treated joints was lower than that in control joints. However, under the stimulation of a cold environment, the sympathetic nerves of the CFA group were excited and secreted various vasodilatory substances. SP and CGRP participated in the stabilization of blood flow in the synovium after cold stimulation (111). Similarly, blood vessel constriction in the inflammation site was most obvious within 0 - 2 minutes after cold stimulation, and then gradually returned to the baseline level. The initial cold-induced vasoconstriction was mediated via TRPA1-dependent superoxide production, and the subsequent restorative blood flow component was also dependent on TRPA1 activation being mediated by sensory nerve-derived dilator neuropeptides CGRP and SP, and also NOS-derived NO (112, 113). Therefore, blood vessels in the inflamed joint will have a process of the first contraction and then relaxation after being cold, and different experimental detection points will have discrepant results. Increased blood flow is due to the effects of TRPA1 and vasodilatory substances, which also cause hypersensitivity to pain.

5.1.2 TRPM8 in the perception of cold and collaboration with TRPA1

TRPM8 is a non-selective cationic channel that can be activated by low temperatures and cooling agents, and plays a role in the perception of cold environments. The response of sensory neurons and intact sensory nerve fibers in TRPM8-deficient mice to cold was significantly weakened in vitro (114, 115). Cold pain associated with CFA-induced inflammation was significantly attenuated in TRPM8(-/-) mice (116). However, one study showed that TRPA1 mediated cold pain in CFA-induced arthritis, but TRPM8 had no effect. The expression of TRPA1, but not TRPM8, increased in CFA-induced inflammation, and knockdown of the TRPA1 gene prevented and reversed inflammation-induced cold hyperalgesia (117). A few experiments found that the threshold of TRPM8 activation was 25°C, consistent with the pleasant/cool feeling induced by menthol products and so, had no effect on cold pain. Different from the above view, TRPM8 and TRPA1 had synergistic effects on cold nociceptive perception (118). A group of researchers found that CFA-induced inflammatory cold pain was selectively mediated by glial cell line derived neurotrophic factor family receptors (GFRα3), which were expressed in a subpopulation of TRPM8 sensory neurons that act as cold nociceptors (119, 120). They then provided new insight that the neurogenic inflammation upstream of the GFRα3 and TRPM8 promoted TRPA1’s perception of cold pain, which was in a TRPM8-dependent manner (121). According to the above, TRPM8 joins hands with TRPA1 and serve an important role in cold pain in CFA-induced arthritis.

5.2 TRPs in inflammatory pain (heat and mechanical)

Thermal (heat) and mechanical noxious stimuli are detected by specialized nerve endings, which transform the stimuli into electrical signals and convey the stimuli to the central nervous system, causing thermal and mechanical pain. The basis for hyperalgesia is the sensitization of the nociceptive system to stimuli (hypersensitivity), moreover, the threshold for the excitation of nociceptive neurons is lowered(low threshold), and therefore, the responses to noxious stimuli are heightened (122). RA patients suffer from hypersensitivity to heat and mechanical joint pain caused by inflammatory factors and joint movement. In the following sections, we emphasize the introduction of inflammatory thermal (heat) and mechanical pain, mainly on the mechanisms involved in TRPV1 and TRPA1.

5.2.1 Role of TRPV1 in inflammatory pain

The TRPV1 is expressed on sensory neurons and can sense changes of heat (temperature >43°C), proinflammatory substances, lipoxygenase products, endocannabinoids, protons, and so on (123). TRPV1 is involved in two typical inflammatory hyperalgesia: thermal and mechanical pain. Peripheral distribution of TRPV1 played a major role in CFA-induced thermal hyperalgesia, but to a lesser extent in mechanical hyperalgesia. While, spinal cord distribution of TRPV1 act as an important role in the perception of both types of hyperalgesia (124).

There was a significant interaction between the inflammatory state and TRPV1 activation, resulting in inflammatory pain perception (125). Firstly, TRPV1 receptor protein was upregulated during CFA-induced inflammation, and mediated inflammatory hyperalgesia (126–128). Secondly, the activation of TRPV1 is regulated by its phosphorylation status which is dependent on the balanced actions of protein kinases and protein phosphatases (129). The activity of protein kinases and protein phosphatases are often activated or inhibited in inflammatory circumstances. In CFA-induced arthritis models, increased expression of phosphorylated protein kinase A phosphorylated TRPV1 and sensitized it, resulting in inflammatory mechanical and thermal pain (130). Furthermore, evidence showed that TRPV1 phosphorylation by Cdk5(Cyclin-dependent kinase 5, an important serine/threonine kinase) promoted the distribution of TRPV1 in the plasma membrane and contributed to thermal hyperalgesia during inflammation post-CFA (131).

5.2.2 Role of TRPA1 in inflammatory pain

At the beginning of this section, we focused on the role of TRPA1 in cold pain sensitivity in RA patients. In addition, it has been shown to play a role in mediating thermal (heat) and mechanical pain sensations in inflamed joints. One study showed that TRPA1 played a key role in both thermal and mechanical pain in CFA-induced arthritis (132). Similarly, application of the selective TRPA1 antagonist HC-030031 could significantly reduce mechanical hyperalgesia of the CFA-injected joint (108). Furthermore, intraarticular injection of CFA in TRPA1-/- mice inducing ipsilateral mechanical hyperalgesia was maintained for only 24 hours compared to 3 weeks in TRPA1 WT mice (133). These studies indicate that TRPA1 also takes part in inflammatory mechanical hyperalgesia and the transition from acute to chronic pain.

5.2.3 The “love and kill” relationship between TRPV1 and TRPA1 in inflammatory pain

It is well manifested that TRPA1 is co-expressed in 60 – 75% of TRPV1-expressing sensory C-fiber nerves (107, 134). In addition, they interact with each other in pain perception at the central level. The frequency of spontaneous excitatory postsynaptic currents (EPSCs) in lamina I dorsal horn neurons were enhanced by CFA treatment, which could be attenuated with the employment of a specific TRPA1 or TRPV1 antagonist. TRPA1 mediated the increased presynaptic glutamate release to lamina I neurons and TRPV1 contributes to increased glutamatergic input in chronic inflammatory pain perception. Therefore, TRPA1 and TRPV1 cooperate at the spinal cord level, leading to the maintenance of chronic inflammatory pain (135).

Consistent with the above report on the involvement of TRPA1 in inflammatory mechanical hyperalgesia, in the CFA-induced inflammatory pain model, Tmem100 CKO mice showed attenuated mechanical hyperalgesia, indicating that TRPA1 participated in mechanical hyperalgesia. In DRG neurons, Tmem100 could be co-expressed with TRPA1 and TRPV1 and form a complex, which attenuated TRPV1’s inhibition of TRPA1, thereby selectively enhancing TRPA1 activities. Tmem100-3Q, a Tmem100 mutant had the opposite effect which enhanced the association of TRPA1 and TRPV1 and strongly inhibited the activity of TRPA1 in a TRPV1-dependent way. Tmem100-3Q CPP could mimic Tmem100-3Q’s effect and inhibits persistent pain by TRPA1. So, Tmem100-3Q CPP or molecules that have similar functions may be promising pain therapy for alleviating mechanical hyperalgesia (136). However, study also shown that reducing the link between TRPA1 and TRPV1 led to the reduction of TRPA1 function. They found that reduction of the A1-V1 complex significantly reduced TRPA1 sensitization and CFA-induced hypersensitivity (137). These findings suggest that there are certain functional molecules between TRPA1 and TRPV1 during they participate in the development and maintenance of hyperalgesia. Drugs or therapeutic strategies which are able to directly or indirectly target their interactions may shed new lights on potential analgesics and may have minor if any side effects.

5.3 Role of inflammatory mediators and neuropeptides in TRPs mediating inflammatory pain

Different pro-inflammatory cytokines are not only participants in inflammation, what’s more, each cytokine has its profile of effects on inflammatory pain. And most importantly, the formation of pain perception is determined by a variety of cytokines, and keep in mind that different stimuli and multiple pain receptors exist and work at the same time. Multiple sensory receptors, including TRPs, interact and influence each other to make certain pain perceptions. Due to the important role of TNF-α in RA, we will elaborate on the correlation between TNF-α and TRPs in mediating inflammatory pain. The influences of other inflammatory substances on TRPs in inflammatory pain perception are summarized in Table 1 .

Table 1

Summary of RA related inflammatory stimuli on different subtypes of TRPs in inflammatory pain perception.

Subfamilies	Cytokines	Models of arthritis	Mechanisms of interaction between inflammatory stimuli and TRPs	nociceptive response	References
TRPV1	IL-1ROSROS	K/BxN serum transfer-induced arthritisAIACarrageenan-induced arthritisCFA-induced hyperalgesia ratsAIA rats	IL-1 receptor (IL-1R1) was highly expressed by a subpopulation of TRPV1+ dorsal root ganglion neurons.IL-1β up-regulated the expression of TRPV-1, and the expression of IL-1R1 in the lumbar DRGs was significantly increased.NADPH oxidase increased the production of ROS which promoted the level of PKC in DRG neurons, then activating the TRPV1.Activated Nox1/Nox4-ROS pathway sensitized TRPV1-dependent Ca²⁺ influx and CGRP releasing.FLS from AIA rats induced upregulation of pain-related receptors(neurokinin 1 receptor、TRPV1 receptor) in sensory neurons.	Increased mechanical allodyniaIncreased thermal hyperalgesiaIncreased thermal and mechanical hyperalgesiaIncreased mechanical hyperalgesiaIncreased thermal hyperalgesia	(138)(139)(140, 141)(142)(143)
TRPA1		RA patients	TRPA1 expression on peripheral blood leukocytes was increased.	Increased VAS pain scale	(144)
TRPC3	immune complex	Antigen-induced arthritis (AIA)	IgG-IC activated FcγRI which triggered TRPC channels through the Syk-PLC-IP₃ pathway on DRG neurons.	Increased mechanical and thermal hyperalgesia	(145, 146)
TRPC5	Lysophosphatidylcholine (LPC)	CFA mice	The elevated concentrations of LPC-induced TRPC5-dependent neuronal activity in CFA-induced arthritis.	Increased mechanical hyperalgesia	(147)
TRPC5		CFA mice	The expression of TRPC5 was negatively correlated with the concentrations of inflammatory mediators and cytokines.	Decreased thermal andmechanical hyperalgesia	(148)
TRPV4	Protease-activated receptor-2 (PAR2)	Elastase stimulated mouse	Elastase induced a PAR (2)- and TRPV4-mediated influx of extracellular Ca²⁺ in nociceptors.	Increased mechanical hyperalgesia	(149)
TRPV4	IL-17A		IL-17A increased the expression of TRPV4.	Increased mechanical hyperalgesia	(150)
TRPV1TRPA1	Oxidized phospholipids (OxPL)	CIA	OxPL evoked the CGRP release and activated TRPV1 and TRPA1.	Increased thermal andmechanical hyperalgesia	(151)
TRPV1TRPC6	LPS	LPS-induced inflammatory	TRPV-1-mediated NLRP3 inflammasome activation.LPS-induced neutrophil and monocyte recruitment and promoted the activation of nociceptor TRPV1 and TRPA1.	Increased thermal hyperalgesiaIncreased mechanical andthermal hyperalgesia	(74, 152)(153)
TRPV1, P2X3R	Leukotrienes (LTs)	Mice pretreated with LTC4	Some types of LTs co-expressed in TRPV1 and P2X3-positive neurons.	Increased thermal hyperalgesia	(154)

5.3.1 Differences between TRPA1 and TRPV1 in peripheral and central inflammatory perception of TNF-α induced inflammatory pain

TRPV1 are also downstream targets for various pro-inflammatory and pain-producing agents such as IL-1β and TNF-α. These compounds initiate an allosteric modification of the TRPV1 channel protein, resulting in an increase in the probability of channel opening or TRPV1 sensitized.

Paw withdrawal latency (PWL)was always taken as the thermal hyperalgesic threshold (155). TRPV1-/- mice had significantly higher baseline PWL than WT mice post-injection of TNF-a, the WT mice exhibited significantly reduced PWL compared to the TRPV1-/-mice, indicating that TNF-a induced thermal hyperalgesia was TRPV1 dependent. Moreover, contralateral uninjured hind paws also had thermal pain which was TRPV1-dependent, too. In addition to this, the local IL-1β generation in the contralateral paw, PKC and COX-2-derived prostaglandins were essential for the development of bilateral hyperalgesia (10). Researchers also concluded that most of the DRG neurons expressed the TNFR1 also expressed the TRPV1 receptor. TNF-α could up-regulate the expression of TRPV1 receptor, thus causing thermal hyperalgesia (156).

Some researchers completed their study which demonstrated that TNFα-mediated thermal hyperalgesia involves TRPV1 (10). They then wanted to investigate the role of TRPV1 and TRPA1 in the TNF-α induced mechanical hyperalgesia. By studying several models of inflammatory arthritis, they found that central distribution of TRPV1 was involved in TNF-α-induced mechanical hyperalgesia. The peripheral distribution of TRPA1 not only played in the occurrence of TNF-α induced mechanical hyperalgesia, but also act as a key role in the maintenance of CFA-induced mechanical hyperalgesia (133). In line with this result, researchers showed for the first time that TRPA1 has an important peripheral role in TNF-α-mediated mechanical hyperalgesia, which is different from TRPV1 distributed in the central nervous system in mechanical hyperalgesia (157). Thus, these studies present evidence that both TRPV1 and TRPA1 participate in TNF-α medicated inflammatory pain, but they may tend to have their separate strong points in peripheral and central inflammatory perception, which may direct us to explore the corresponding drug. Just as important, anti-TNF-α therapy has also been proven to have analgesic effects.

5.3.2 TRPs collaborate with neuropeptides in perceiving inflammatory pain and promoting inflammation

Neuropeptide-expressing small-diameter sensory neurons are thought to be vital in inducing inflammatory hyperalgesic responses in inflammation. The CGRP peptide expression was increased after CFA injection compared to the control group and contributed to inflammatory hyperalgesia (158, 159). In arthritis mice, Concomitant with the disease progression, there was a significant increase in the density of CGRP+ nerve fibers in the synovium, as well as an enhancement in joint pain-related behaviors compared with the sham-injected mice (104, 160). CGRP-positive neurons partially overlapped with TRPV1 in DRG neurons. As a mutual, activated TRPV1 up-regulated CGRP expression, leading to the induction of inflammation pain (161). TRPV1 expression was also increased in small peptidergic (CGRP positive) neurons after injection of CFA and played a role in chronic thermal hyperalgesia and mechanical pain (126).

In addition to their role in pain perception, CGRP-secreting nerve fibers also contribute to RA inflammation. As highlighted and discussed at the beginning of this paper, CGRP is an extremely potent vasodilator, leading to edema formation and recruitment of inflammatory cells to the local sites. It also significantly elevated the production of inflammatory cytokines (such as IL-1β, IL-6 and TNF-α) in RA patients (162, 163). Neuropeptides may strongly enhance TRPV1 expression in RA synoviocytes. SP or CGRP in combination with TRPV1 could powerfully motivate the expression of pro-inflammatory cytokines IL-6 and IL-8 in RA synoviocytes, having no effects on healthy synoviocytes (164).

Neural TRPs have the potential role to orchestrate inflammatory signals with neuropeptides released by neurons within the synovial microenvironment of the RA-inflamed joints. Various inflammatory mediators and neuropeptides sensitize and regulate the activation threshold of TRPs, causing inflammatory pain. In turn, TRPs located on neurons not only sense pain, but also boost inflammation by promoting the production of pro-inflammatory neuropeptides. These findings help us understand the neuro-inflammation mutually influenced pain aggravation, as well as inflammation persistence. Moreover, it also proves that TRPs can be used as a new target for clinical treatment of RA.

Conclusion

To sum up, evidence suggests the multiple functions of TRPs in RA pathogenesis, including joint swelling, neutrophil TEM and activation, angiogenesis and pain hyperalgesia. Ca²⁺ signals or potential induced by TRPs play a central role in transmitting inflammatory signals and amplifying inflammatory pain. TNF-α, VEGF and ROS are inflammatory molecules enriched in the joint microenvironment, acting on TRPs on ECs to increase the vascular permeability, which is the prerequisite for joint edema. TRPs-mediated Ca²⁺ influx into neutrophils plays an important role in their adhesion and TEM. Ca²⁺ signals caused by TRPs on neutrophils catalyze PADs activity and NETs formation, which enhancing the amount of auto-antigen in RA and leading to the formation of destructive autoantibodies ACPA. Though the relationship between TRPs and RA-FLS proliferation or apoptosis yet needs further investigation, TRPs can affect ECs migration and angiogenesis. Various inflammatory mediators and neuropeptides can sensitize and modulate the activation threshold of TRPs, resulting in the development of pain behaviors. TRPs can not only perceive cold and inflammatory stimuli but also communicate with pro-inflammation neuropeptides released by neurons within the RA-inflamed joints, resulting in persistent inflammation and pain hyperalgesia.

With scientists’ endeavors to explore TRPs over the years, many drugs targeting TRPs and antagonists interacting with inflammatory factors are in preclinical studies. Preclinical studies on TRPV1 as an analgesic have made fruitful progress. As TRPV1 agonists, capsaicin substances can cause TRPV1 desensitization of nerve endings when applied in a larger dose in the periphery, thus playing an analgesic role. Patches, creams, and sprays containing capsaicin have not only shown good analgesic effects in preclinical studies on neuralgia (165), joint pain (166), etc., but also have relatively few side effects. Antagonists targeting TRPV1 have significant analgesic effects, but blocking TRPV1 impairs the body’s perception of heat, leading to significant hyperthermia side effects (167). Therefore, the current direction of research is toward the development of antagonists that both reduce pain and less affect the body’s perception of temperature changes (168). At present, many synthetic antagonists for TRPA1 are gradually appearing, including Xanthine derivatives (HC-030031) and oxime derivative, which have been described in recent articles (169). From preclinical data, oxidative stress and activation of Schwann cell TRPA1 may serve as new targets for TRPA1 antagonists to relieve chronic pain in models of pain disorders. Studies shown that botulinum toxins (BoNTs) as a kind of neurotoxins had the ability to suppress the increase of neuropeptides (170). BoNTs acted as an analgesic by reducing TRPV1 expression (171). It not only presented analgesic effects in preclinical arthritis pain models, but also had very few side effects (172). Pre-clinical data on drugs derived from natural ingredients targeting TRPs have also made some progress. Tanshinone IIA (TIIA) is an important component of traditional Chinese medicine Danshen, which has achieved good curative effect in the treatment of nervous circulatory system. Studies have proved that it inhibited the release of inflammatory factors and reduced the expression of TRPV1 in the nervous system so as to reduce inflammation and anti-nociceptive pain in inflammatory arthritis (173). In addition, Paeoniflorin inhibited TRPV1 activation, thus exerting anti-inflammatory and analgesic effects without the hyperthermia side effects associated with traditional TRPV1 antagonists (174). S-(+)-dicentrine derived from camphor plants, reduced cold and mechanical pain in inflammatory mice by inhibiting TRPA1 activation (175). Not only has the anti-inflammatory and analgesic effect of traditional Chinese medicine (TCM), but other TCM methods have also shown a pleasing effect in relieving pain. The effect of electroacupuncture on pain relief has been widely recognized, but the specific mechanism is still unclear. Recent studies manifested that electroacupuncture reduced joint pain by interacting with TRPV1 (176). In addition, different acupuncture intensities and the distribution of nerve fibers where TRPV1 was located also vary the analgesic effect and the body parts relieved by electroacupuncture (177). Studies have shown inspiring efficacy in anti-inflammation and analgesic, although there are some side effects. This encourages us to continue to explore the mechanisms of TRPs about the unknown to better relieve the pain and suffering of RA patients.

Author contributions

MN reviewed the literature and wrote the initial draft. MN, PL, and LB designed the article and critically revised the manuscript. FZ and RC collected the data. All authors have approved the manuscript and agreed to the published version of the manuscript.

Conflict of interest

The authors declare that the review was in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher’s note

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References 1 van de Sande

de Hair

van der Leij

Klarenbeek

Bos

Smith

. Different stages of rheumatoid arthritis: Features of the synovium in the preclinical phase. Ann Rheum Dis (2011) 70(5):772–7. doi: 10.1136/ard.2010.139527 2 van Oosterhout

Bajema

Levarht

Toes

Huizinga

van Laar

. Differences in synovial tissue infiltrates between anti-cyclic citrullinated peptide-positive rheumatoid arthritis and anti-cyclic citrullinated peptide-negative rheumatoid arthritis. Arthritis Rheum (2008) 58(1):53–60. doi: 10.1002/art.23148 3 Myasoedova

Crowson

Kremers

Therneau

Gabriel

. Is the incidence of rheumatoid arthritis rising?: Results from olmsted county, minnesota, 1955-2007. Arthritis Rheum (2010) 62(6):1576–82. doi: 10.1002/art.27425 4 Jager

Murthy

Schmidt

Hahn

Strobel

Peters

. Calcium-sensing receptor-mediated NLRP3 inflammasome response to calciprotein particles drives inflammation in rheumatoid arthritis. Nat Commun (2020) 11(1):4243. doi: 10.1038/s41467-020-17749-6 5 Nadolni

Immler

Hoelting

Fraticelli

Ripphahn

Rothmiller

. TRPM7 kinase is essential for neutrophil recruitment and function via regulation of Akt/mTOR signaling. Front Immunol (2020) 11:606893. doi: 10.3389/fimmu.2020.606893 6 Wang

Rong

Wang

Ren

Chen

Jia

. CD147 up-regulates calcium-induced chemotaxis, adhesion ability and invasiveness of human neutrophils via a TRPM-7-mediated mechanism. Rheumatol (Oxford) (2014) 53(12):2288–96. doi: 10.1093/rheumatology/keu260 7 Zhou

Chen

Wei

Tang

. TRPM7 channel inhibition attenuates rheumatoid arthritis articular chondrocyte ferroptosis by suppression of the PKCalpha-NOX4 axis. Redox Biol (2022) 55:102411. doi: 10.1016/j.redox.2022.102411 8 Ma

Yang

Chen

Wei

Ding

Zhou

. Blockade of TRPM7 alleviates chondrocyte apoptosis and articular cartilage damage in the adjuvant arthritis rat model through regulation of the indian hedgehog signaling pathway. Front Pharmacol (2021) 12:655551. doi: 10.3389/fphar.2021.655551 9 Zhu

Wang

Pan

Yang

Sun

Wang

. Involvement of transient receptor potential melastatin-8 (TRPM8) in menthol-induced calcium entry, reactive oxygen species production and cell death in rheumatoid arthritis rat synovial fibroblasts. Eur J Pharmacol (2014) 725:1–9. doi: 10.1016/j.ejphar.2014.01.001 10 Russell

Fernandes

Courade

Keeble

Brain

. Tumour necrosis factor alpha mediates transient receptor potential vanilloid 1-dependent bilateral thermal hyperalgesia with distinct peripheral roles of interleukin-1beta, protein kinase c and cyclooxygenase-2 signalling. Pain (2009) 142(3):264–74. doi: 10.1016/j.pain.2009.01.021 11 Lowin

Straub

. Cannabinoid-based drugs targeting CB1 and TRPV1, the sympathetic nervous system, and arthritis. Arthritis Res Ther (2015) 17(1):226. doi: 10.1186/s13075-015-0743-x 12 Thakore

Earley

. Transient receptor potential channels and endothelial cell calcium signaling. Compr Physiol (2019) 9(3):1249–77. doi: 10.1002/cphy.c180034 13 Wu

Sweet

Clapham

International Union of Basic and Clinical Pharmacology LXXVI . Current progress in the mammalian TRP ion channel family. Pharmacol Rev (2010) 62(3):381–404. doi: 10.1124/pr.110.002725 14 Nilius

Szallasi

. Transient receptor potential channels as drug targets: from the science of basic research to the art of medicine. Pharmacol Rev (2014) 66(3):676–814. doi: 10.1124/pr.113.008268 15 Pan

Yang

Reinach

. Transient receptor potential (TRP) gene superfamily encoding cation channels. Hum Genomics (2011) 5(2):108–16. doi: 10.1186/1479-7364-5-2-108 16 Hardie

. A brief history of trp: Commentary and personal perspective. Pflugers Arch (2011) 461(5):493–8. doi: 10.1007/s00424-011-0922-9 17 Kazandzhieva

Mammadova-Bach

Dietrich

Gudermann

Braun

. TRP channel function in platelets and megakaryocytes: Basic mechanisms and pathophysiological impact. Pharmacol Ther (2022) 237:108164. doi: 10.1016/j.pharmthera.2022.108164 18 Salvador

Arranz

Francisco

Cordoba

Punzon

Llamas

. Modulation of endothelial function by toll like receptors. Pharmacol Res (2016) 108:46–56. doi: 10.1016/j.phrs.2016.03.038 19 Paria

Vogel

Ahmmed

Alamgir

Shroff

Malik

. Tumor necrosis factor-alpha-induced TRPC1 expression amplifies store-operated Ca2+ influx and endothelial permeability. Am J Physiol Lung Cell Mol Physiol (2004) 287(6):L1303–13. doi: 10.1152/ajplung.00240.2004 20 Komarova

Malik

. Regulation of endothelial permeability via paracellular and transcellular transport pathways. Annu Rev Physiol (2010) 72:463–93. doi: 10.1146/annurev-physiol-021909-135833 21 Minshall

Malik

. Transport across the endothelium: Regulation of endothelial permeability. Handb Exp Pharmacol (2006) 176(Pt 1):107–44. doi: 10.1007/3-540-32967-6_4 22 Mehta

Malik

. Signaling mechanisms regulating endothelial permeability. Physiol Rev (2006) 86(1):279–367. doi: 10.1152/physrev.00012.2005 23 Weber

Han

Tauseef

Birnbaumer

Mehta

Muller

. TRPC6 is the endothelial calcium channel that regulates leukocyte transendothelial migration during the inflammatory response. J Exp Med (2015) 212(11):1883–99. doi: 10.1084/jem.20150353 24 Yao

Garland

. Recent developments in vascular endothelial cell transient receptor potential channels. Circ Res (2005) 97(9):853–63. doi: 10.1161/01.RES.0000187473.85419.3e 25 Bon

Beech

. In pursuit of small molecule chemistry for calcium-permeable non-selective TRPC channels – mirage or pot of gold? Br J Pharmacol (2013) 170(3):459–74. doi: 10.1111/bph.12274 26 Yip

Chan

Leung

Kwan

Liu

Huang

. Expression of TRPC homologs in endothelial cells and smooth muscle layers of human arteries. Histochem Cell Biol (2004) 122(6):553–61. doi: 10.1007/s00418-004-0720-y 27 Ambudkar

de Souza

Ong

. TRPC1, Orai1, and STIM1 in SOCE: Friends in tight spaces. Cell Calcium (2017) 63:33–9. doi: 10.1016/j.ceca.2016.12.009 28 Sundivakkam

Freichel

Singh

Yuan

Vogel

Flockerzi

. The ca (2+) sensor stromal interaction molecule 1 (STIM1) is necessary and sufficient for the store-operated ca (2+) entry function of transient receptor potential canonical (TRPC) 1 and 4 channels in endothelial cells. Mol Pharmacol (2012) 81(4):510–26. doi: 10.1124/mol.111.074658 29 Earley

Brayden

. Transient receptor potential channels in the vasculature. Physiol Rev (2015) 95(2):645–90. doi: 10.1152/physrev.00026.2014 30 Montell

Birnbaumer

Flockerzi

. The TRP channels, a remarkably functional family. Cell (2002) 108(5):595–8. doi: 10.1016/s0092-8674(02)00670-0 31 Chen

Sooch

Demaree

White

Obukhov

. Transient receptor potential canonical (TRPC) channels: Then and now. Cells (2020) 9(9):1983. doi: 10.3390/cells9091983 32 Guo

Zhao

Zhang

Xiao

Yan

Liu

. Elucidation of the anti-inflammatory mechanism of er miao san by integrative approach of network pharmacology and experimental verification. Pharmacol Res (2022) 175:106000. doi: 10.1016/j.phrs.2021.106000 33 Clanchy

FIL

Williams

. Ibudilast inhibits chemokine expression in rheumatoid arthritis synovial fibroblasts and exhibits immunomodulatory activity in experimental arthritis. Arthritis Rheumatol (2019) 71(5):703–11. doi: 10.1002/art.40787 34 Mahnashi

Jabbar

Alamgeer Irfan

Asim

Akram

. Venlafaxine demonstrated anti-arthritic activity possibly through down regulation of TNF-α, IL-6, IL-1β, and COX-2. Inflammopharmacology (2021) 29(5):1413–25. doi: 10.1007/s10787-021-00849-0 35 Yokota

Sato

Miyazaki

Aizaki

Tanaka

Sekikawa

. Characterization and function of tumor necrosis factor and interleukin-6-Induced osteoclasts in rheumatoid arthritis. Arthritis Rheumatol (2021) 73(7):1145–54. doi: 10.1002/art.41666 36 Paria

Malik

Kwiatek

Rahman

May

Ghosh

. Tumor necrosis factor-alpha induces nuclear factor-kappaB-dependent TRPC1 expression in endothelial cells. J Biol Chem (2003) 278(39):37195–203. doi: 10.1074/jbc.M304287200 37 Paria

Bair

Xue

Malik

Tiruppathi

. Ca2+ influx induced by protease-activated receptor-1 activates a feed-forward mechanism of TRPC1 expression via nuclear factor-kappaB activation in endothelial cells. J Biol Chem (2006) 281(30):20715–27. doi: 10.1074/jbc.M600722200 38 Luo

Liu

Zhang

Wei

Zeng

. (CGA)-derived polypeptide (CGA(47-66)) inhibits TNF-α-induced vascular endothelial hyper-permeability through SOC-related ca (2+) signaling. Peptides (2020) 131:170297. doi: 10.1016/j.peptides.2020.170297 39 Solfietti

Binello

Stella

Bazzan

Salierno

Roccatello

. Thrombin generation assay: interactions between chronic inflammation and haemostasis in patients with autoimmune diseases. Clin Exp Rheumatol (2016) 34(5):925–8. 40 Sokolov

Acquasaliente

Kostevich

Frasson

Zakharova

Pontarollo

. Thrombin inhibits the anti-myeloperoxidase and ferroxidase functions of ceruloplasmin: relevance in rheumatoid arthritis. Free Radic Biol Med (2015) 86:279–94. doi: 10.1016/j.freeradbiomed.2015.05.016 41 Ahmmed

Mehta

Vogel

Holinstat

Paria

Tiruppathi

. Protein kinase calpha phosphorylates the TRPC1 channel and regulates store-operated Ca2+ entry in endothelial cells. J Biol Chem (2004) 279(20):20941–9. doi: 10.1074/jbc.M313975200 42 Kini

Chavez

Mehta

. A new role for PTEN in regulating transient receptor potential canonical channel 6-mediated Ca2+ entry, endothelial permeability, and angiogenesis. J Biol Chem (2010) 285(43):33082–91. doi: 10.1074/jbc.M110.142034 43 Jakubczyk

Dec

Kaldunska

Kawczuga

Kochman

Janda

. Reactive oxygen species - sources, functions, oxidative damage. Pol Merkur Lekarski (2020) 48(284):124–7. 44 Khojah

Ahmed

Abdel-Rahman

Hamza

. Reactive oxygen and nitrogen species in patients with rheumatoid arthritis as potential biomarkers for disease activity and the role of antioxidants. Free Radic Biol Med (2016) 97:285–91. doi: 10.1016/j.freeradbiomed.2016.06.020 45 Hoffmann

Griffiths

. The dual role of reactive oxygen species in autoimmune and inflammatory diseases: evidence from preclinical models. Free Radic Biol Med (2018) 125:62–71. doi: 10.1016/j.freeradbiomed.2018.03.016 46 Phull

Nasir

Haq

Kim

. Oxidative stress, consequences and ROS mediated cellular signaling in rheumatoid arthritis. Chem Biol Interact (2018) 281:121–36. doi: 10.1016/j.cbi.2017.12.024 47 da Fonseca

LJS

Nunes-Souza

Goulart

MOF

Rabelo

. Oxidative stress in rheumatoid arthritis: What the future might hold regarding novel biomarkers and add-on therapies. Oxid Med Cell Longev (2019) 2019:7536805. doi: 10.1155/2019/7536805 48 He

Talukder

MAH

Gao

. Oxidative stress and microvessel barrier dysfunction. Front Physiol (2020) 11:472. doi: 10.3389/fphys.2020.00472 49 Hecquet

Ahmmed

Vogel

Malik

. Role of TRPM2 channel in mediating H2O2-induced Ca2+ entry and endothelial hyperpermeability. Circ Res (2008) 102(3):347–55. doi: 10.1161/CIRCRESAHA.107.160176 50 Fava

Olsen

Spencer-Green

Yeo

Berse

. Vascular permeability factor/endothelial growth factor (VPF/VEGF): accumulation and expression in human synovial fluids and rheumatoid synovial tissue. J Exp Med (1994) 180(1):341–6. doi: 10.1084/jem.180.1.341 51 Kim

Kim

Cho

Lee

. The effect of vascular endothelial growth factor on osteoclastogenesis in rheumatoid arthritis. PloS One (2015) 10(4):e0124909. doi: 10.1371/journal.pone.0124909 52 Biscetti

Flex

Pecorini

Angelini

Arena

Stigliano

. The role of high-mobility group box protein 1 in collagen antibody-induced arthritis is dependent on vascular endothelial growth factor. Clin Exp Immunol (2016) 184(1):62–72. doi: 10.1111/cei.12758 53 Ikeda

Hosoda

Hirose

Okada

Ikeda

. Expression of vascular endothelial growth factor isoforms and their receptors flt-1, KDR, and neuropilin-1 in synovial tissues of rheumatoid arthritis. J Pathol (2000) 191(4):426–33. doi: 10.1002/1096-9896 (2000)9999:9999<::Aid-path649>3.0.Co;2-e 54 Chen

Hsu

Huang

Wang

Liu

. CCN1 promotes VEGF production in osteoblasts and induces endothelial progenitor cell angiogenesis by inhibiting miR-126 expression in rheumatoid arthritis. J Bone Miner Res (2017) 32(1):34–45. doi: 10.1002/jbmr.2926 55 Lamalice

Le Boeuf

Huot

. Endothelial cell migration during angiogenesis. Circ Res (2007) 100(6):782–94. doi: 10.1161/01.RES.0000259593.07661.1e 56 Hamdollah Zadeh

Glass

Magnussen

Hancox

Bates

. VEGF-mediated elevated intracellular calcium and angiogenesis in human microvascular endothelial cells in vitro are inhibited by dominant negative TRPC6. Microcirculation (2008) 15(7):605–14. doi: 10.1080/10739680802220323 57 Bates

. Vascular endothelial growth factors and vascular permeability. Cardiovasc Res (2010) 87(2):262–71. doi: 10.1093/cvr/cvq105 58 Jho

Mehta

Ahmmed

Gao

Tiruppathi

Broman

. Angiopoietin-1 opposes VEGF-induced increase in endothelial permeability by inhibiting TRPC1-dependent Ca2 influx. Circ Res (2005) 96(12):1282–90. doi: 10.1161/01.RES.0000171894.03801.03 59 Cheng

James

Foster

Hancox

Bates

. VEGF activates receptor-operated cation channels in human microvascular endothelial cells. Arterioscler Thromb Vasc Biol (2006) 26(8):1768–76. doi: 10.1161/01.ATV.0000231518.86795.0f 60 Immler

Simon

Sperandio

. Calcium signalling and related ion channels in neutrophil recruitment and function. Eur J Clin Invest (2018) 48(Suppl 2):e12964. doi: 10.1111/eci.12964 61 Gong

Liu

Jiang

Zhou

. DAMP-sensing receptors in sterile inflammation and inflammatory diseases. Nat Rev Immunol (2020) 20(2):95–112. doi: 10.1038/s41577-019-0215-7 62 Phillipson

Kubes

. The neutrophil in vascular inflammation. Nat Med (2011) 17(11):1381–90. doi: 10.1038/nm.2514 63 Ley

Laudanna

Cybulsky

Nourshargh

. Getting to the site of inflammation: the leukocyte adhesion cascade updated. Nat Rev Immunol (2007) 7(9):678–89. doi: 10.1038/nri2156 64 Sadik

Kim

Luster

. Neutrophils cascading their way to inflammation. Trends Immunol (2011) 32(10):452–60. doi: 10.1016/j.it.2011.06.008 65 Arancibia

Beltran

Aguirre

Silva

Peralta

Malinarich

. Toll-like receptors are key participants in innate immune responses. Biol Res (2007) 40(2):97–112. doi: 10.4067/s0716-97602007000200001 66 Zeytun

Chaudhary

Pardington

Cary

Gupta

. Induction of cytokines and chemokines by toll-like receptor signaling: strategies for control of inflammation. Crit Rev Immunol (2010) 30(1):53–67. doi: 10.1615/critrevimmunol.v30.i1.40 67 Lindemann

Rossaint

Najder

Schimmelpfennig

Hofschröer

Wälte

. Intravascular adhesion and recruitment of neutrophils in response to CXCL1 depends on their TRPC6 channels. J Mol Med (Berl) (2020) 98(3):349–60. doi: 10.1007/s00109-020-01872-4 68 Lindemann

Strodthoff

Horstmann

Nielsen

Jung

Schimmelpfennig

. TRPC1 regulates fMLP-stimulated migration and chemotaxis of neutrophil granulocytes. Biochim Biophys Acta (2015) 1853(9):2122–30. doi: 10.1016/j.bbamcr.2014.12.037 69 Wright

Lyon

Chapman

Moots

Edwards

. Rheumatoid arthritis synovial fluid neutrophils drive inflammation through production of chemokines, reactive oxygen species, and neutrophil extracellular traps. Front Immunol (2020) 11:584116. doi: 10.3389/fimmu.2020.584116 70 Nanki

Shimaoka

Hayashida

Taniguchi

Yonehara

Miyasaka

. Pathogenic role of the CXCL16-CXCR6 pathway in rheumatoid arthritis. Arthritis Rheum (2005) 52(10):3004–14. doi: 10.1002/art.21301 71 Meeuwisse

van der Linden

Rullmann

Allaart

Nelissen

Huizinga

. Identification of CXCL13 as a marker for rheumatoid arthritis outcome using an in silico model of the rheumatic joint. Arthritis Rheum (2011) 63(5):1265–73. doi: 10.1002/art.30273 72 Watanabe

Penfold

Matsuda

Ohyanagi

Kaneko

Miyabe

. Pathogenic role of CXCR7 in rheumatoid arthritis. Arthritis Rheum (2010) 62(11):3211–20. doi: 10.1002/art.27650 73 Yellin

Paliienko

Balanescu

Ter-Vartanian

Tseluyko

. Randomized, double-blind, placebo-controlled study evaluating the efficacy and safety of MDX-1100, a fully human anti-CXCL10 monoclonal antibody, in combination with methotrexate in patients with rheumatoid arthritis. Arthritis Rheum (2012) 64(6):1730–9. doi: 10.1002/art.34330 74 Lindemann

Umlauf

Frank

Schimmelpfennig

Bertrand

Pap

. TRPC6 regulates CXCR2-mediated chemotaxis of murine neutrophils. J Immunol (2013) 190(11):5496–505. doi: 10.4049/jimmunol.1201502 75 Damann

Owsianik

Poll

Nilius

. The calcium-conducting ion channel transient receptor potential canonical 6 is involved in macrophage inflammatory protein-2-induced migration of mouse neutrophils. Acta Physiol (Oxf) (2009) 195(1):3–11. doi: 10.1111/j.1748-1716.2008.01918.x 76 Wang

Dai

Wang

Jia

Zheng

Ding

. Expression of CD147 (EMMPRIN) on neutrophils in rheumatoid arthritis enhances chemotaxis, matrix metalloproteinase production and invasiveness of synoviocytes. J Cell Mol Med (2011) 15(4):850–60. doi: 10.1111/j.1582-4934.2010.01084.x 77 Nakashima

Hagiwara

Ishigami

Nagata

Asaga

Kuramoto

. Molecular characterization of peptidylarginine deiminase in HL-60 cells induced by retinoic acid and 1alpha,25-dihydroxyvitamin D(3). J Biol Chem (1999) 274(39):27786–92. doi: 10.1074/jbc.274.39.27786 78 Khandpur

Carmona-Rivera

Vivekanandan-Giri

Gizinski

Yalavarthi

Knight

. NETs are a source of citrullinated autoantigens and stimulate inflammatory responses in rheumatoid arthritis. Sci Transl Med (2013) 5(178):178ra40. doi: 10.1126/scitranslmed.3005580 79 Spengler

Lugonja

Ytterberg

Zubarev

Creese

Pearson

. Release of active peptidyl arginine deiminases by neutrophils can explain production of extracellular citrullinated autoantigens in rheumatoid arthritis synovial fluid. Arthritis Rheumatol (2015) 67(12):3135–45. doi: 10.1002/art.39313 80 Arita

Hashimoto

Shimizu

Nakashima

Yamada

Sato

. Structural basis for ca (2+)-induced activation of human PAD4. Nat Struct Mol Biol (2004) 11(8):777–83. doi: 10.1038/nsmb799 81 Hofmann

Obukhov

Schaefer

Harteneck

Gudermann

Schultz

. Direct activation of human TRPC6 and TRPC3 channels by diacylglycerol. Nature (1999) 397(6716):259–63. doi: 10.1038/16711 82 Brechard

Melchior

Plancon

Schenten

Tschirhart

. Store-operated Ca2+ channels formed by TRPC1, TRPC6 and Orai1 and non-store-operated channels formed by TRPC3 are involved in the regulation of NADPH oxidase in HL-60 granulocytes. Cell Calcium (2008) 44(5):492–506. doi: 10.1016/j.ceca.2008.03.002 83 Dang

Stensballe

Boussetta

Raad

Dewas

Kroviarski

. A specific p47phox -serine phosphorylated by convergent MAPKs mediates neutrophil NADPH oxidase priming at inflammatory sites. J Clin Invest (2006) 116(7):2033–43. doi: 10.1172/jci27544 84 Rochael

Guimaraes-Costa

Nascimento

DeSouza-Vieira

Oliveira

Garcia e Souza

. Classical ROS-dependent and early/rapid ROS-independent release of neutrophil extracellular traps triggered by leishmania parasites. Sci Rep (2015) 5:18302. doi: 10.1038/srep18302 85 Muraro

De Souza

Gallo

Da Silva

De Oliveira

Vinolo

MAR

. Respiratory syncytial virus induces the classical ROS-dependent NETosis through PAD-4 and necroptosis pathways activation. Sci Rep (2018) 8(1):14166. doi: 10.1038/s41598-018-32576-y 86 Sur Chowdhury

Giaglis

Walker

Buser

Hahn

Hasler

. Enhanced neutrophil extracellular trap generation in rheumatoid arthritis: analysis of underlying signal transduction pathways and potential diagnostic utility. Arthritis Res Ther (2014) 16(3):R122. doi: 10.1186/ar4579 87 Xia

Wang

. Mechanism of TRPM2 channel gating revealed by cryo-EM. FEBS J (2019) 286(17):3333–9. doi: 10.1111/febs.14939 88 Wang

Dong

Cai

Simaiti

Yang

. Silica nanoparticles induce lung inflammation in mice via ROS/PARP/TRPM2 signaling-mediated lysosome impairment and autophagy dysfunction. Part Fibre Toxicol (2020) 17(1):23. doi: 10.1186/s12989-020-00353-3 89 Kolisek

Beck

Fleig

Penner

. Cyclic ADP-ribose and hydrogen peroxide synergize with ADP-ribose in the activation of TRPM2 channels. Mol Cell (2005) 18(1):61–9. doi: 10.1016/j.molcel.2005.02.033 90 Gorlach

Bertram

Hudecova

Krizanova

. Calcium and ROS: A mutual interplay. Redox Biol (2015) 6:260–71. doi: 10.1016/j.redox.2015.08.010 91 Aleman

Mora

Rosales

. The antibody receptor fc gamma receptor IIIb induces calcium entry via transient receptor potential melastatin 2 in human neutrophils. Front Immunol (2021) 12:657393. doi: 10.3389/fimmu.2021.657393 92 Dogru

Naziroglu

Cig

. Modulator role of infliximab and methotrexate through the transient receptor potential melastatin 2 (TRPM2) channel in neutrophils of patients with rheumatoid arthritis: A pilot study. Arch Med Sci (2019) 15(6):1415–24. doi: 10.5114/aoms.2018.79485 93 Walsh

McWilliams

Turley

Dixon

Fransès

Mapp

. Angiogenesis and nerve growth factor at the osteochondral junction in rheumatoid arthritis and osteoarthritis. Rheumatol (Oxford) (2010) 49(10):1852–61. doi: 10.1093/rheumatology/keq188 94 Ferrara

Gerber

LeCouter

. The biology of VEGF and its receptors. Nat Med (2003) 9(6):669–76. doi: 10.1038/nm0603-669 95 Kanugula

Adapala

Midha

Cappelli

Meszaros

Paruchuri

. Novel noncanonical regulation of soluble VEGF/VEGFR2 signaling by mechanosensitive ion channel TRPV4. FASEB J (2019) 33(1):195–203. doi: 10.1096/fj.201800509R 96 Tsai

Chen

Gong

Liu

Chen

Huang

. CXCL13/CXCR5 axis facilitates endothelial progenitor cell homing and angiogenesis during rheumatoid arthritis progression. Cell Death Dis (2021) 12(9):846. doi: 10.1038/s41419-021-04136-2 97 Antigny

Girardin

Frieden

. Transient receptor potential canonical channels are required for in vitro endothelial tube formation. J Biol Chem (2012) 287(8):5917–27. doi: 10.1074/jbc.M111.295733 98 Ge

Tai

Sun

Zhou

Yang

Cheng

. Critical role of TRPC6 channels in VEGF-mediated angiogenesis. Cancer Lett (2009) 283(1):43–51. doi: 10.1016/j.canlet.2009.03.023 99 Korb

Pavenstadt

Pap

. Cell death in rheumatoid arthritis. Apoptosis (2009) 14(4):447–54. doi: 10.1007/s10495-009-0317-y 100 Elshabrawy

Chen

Volin

Ravella

Virupannavar

Shahrara

. The pathogenic role of angiogenesis in rheumatoid arthritis. Angiogenesis (2015) 18(4):433–48. doi: 10.1007/s10456-015-9477-2 101 Liu

Huang

Zhang

. Inhibition of transient receptor potential canonical 6 attenuates fibroblast-like synoviocytes mediated synovial inflammation and joint destruction in rheumatoid arthritis. Clin Exp Rheumatol (2021) 39(1):115–24. doi: 10.55563/clinexprheumatol/rffvyg 102 Li

Wang

Huang

. Inhibition of transient receptor potential melastatin 7 (TRPM7) channel induces RA FLSs apoptosis through endoplasmic reticulum (ER) stress. Clin Rheumatol (2014) 33(11):1565–74. doi: 10.1007/s10067-014-2599-x 103 Lowin

Bleck

Schneider

Pongratz

. Selective killing of proinflammatory synovial fibroblasts via activation of transient receptor potential ankyrin (TRPA1). Biochem Pharmacol (2018) 154:293–302. doi: 10.1016/j.bcp.2018.05.015 104 Ghilardi

Freeman

Jimenez-Andrade

Coughlin

Kaczmarska

Castaneda-Corral

. Neuroplasticity of sensory and sympathetic nerve fibers in a mouse model of a painful arthritic joint. Arthritis Rheum (2012) 64(7):2223–32. doi: 10.1002/art.34385 105 Hwang

. Current concepts of nociception: nociceptive molecular sensors in sensory neurons. Curr Opin Anaesthesiol (2007) 20(5):427–34. doi: 10.1097/ACO.0b013e3282eff91c 106 Karashima

Talavera

Everaerts

Janssens

Kwan

Vennekens

. TRPA1 acts as a cold sensor in vitro and in vivo . Proc Natl Acad Sci U.S.A. (2009) 106(4):1273–8. doi: 10.1073/pnas.0808487106 107 Story

Peier

Reeve

Eid

Mosbacher

Hricik

. ANKTM1, a TRP-like channel expressed in nociceptive neurons, is activated by cold temperatures. Cell (2003) 112(6):819–29. doi: 10.1016/s0092-8674(03)00158-2 108 da Costa

DSM

Meotti

Andrade

Leal

Motta

Calixto

. The involvement of the transient receptor potential A1 (TRPA1) in the maintenance of mechanical and cold hyperalgesia in persistent inflammation. Pain (2010) 148(3):431–7. doi: 10.1016/j.pain.2009.12.002 109 Horváth

Tékus

Boros

Pozsgai

Botz

Borbély

. Transient receptor potential ankyrin 1 (TRPA1) receptor is involved in chronic arthritis: in vivo study using TRPA1-deficient mice. Arthritis Res Ther (2016) 18:6. doi: 10.1186/s13075-015-0904-y 110 Dunham

Leith

Lumb

Donaldson

. Transient receptor potential channel A1 and noxious cold responses in rat cutaneous nociceptors. Neuroscience (2010) 165(4):1412–9. doi: 10.1016/j.neuroscience.2009.11.065 111 Fernandes

Russell

Alawi

Sand

Liang

Salamon

. Environmental cold exposure increases blood flow and affects pain sensitivity in the knee joints of CFA-induced arthritic mice in a TRPA1-dependent manner. Arthritis Res Ther (2016) 18:7. doi: 10.1186/s13075-015-0905-x 112 Aubdool

Graepel

Kodji

Alawi

Bodkin

Srivastava

. TRPA1 is essential for the vascular response to environmental cold exposure. Nat Commun (2014) 5:5732. doi: 10.1038/ncomms6732 113 Aubdool

Kodji

Abdul-Kader

Heads

Fernandes

Bevan

. TRPA1 activation leads to neurogenic vasodilatation: Involvement of reactive oxygen nitrogen species in addition to CGRP and NO. Br J Pharmacol (2016) 173(15):2419–33. doi: 10.1111/bph.13519 114 Bautista

Siemens

Glazer

Tsuruda

Basbaum

Stucky

. The menthol receptor TRPM8 is the principal detector of environmental cold. Nature (2007) 448(7150):204–8. doi: 10.1038/nature05910 115 Colburn

Lubin

Stone

Jr. Wang

Lawrence

D'Andrea

. Attenuated cold sensitivity in TRPM8 null mice. Neuron (2007) 54(3):379–86. doi: 10.1016/j.neuron.2007.04.017 116 Knowlton

Palkar

Lippoldt

McCoy

Baluch

Chen

. A sensory-labeled line for cold: TRPM8-expressing sensory neurons define the cellular basis for cold, cold pain, and cooling-mediated analgesia. J Neurosci (2013) 33(7):2837–48. doi: 10.1523/JNEUROSCI.1943-12.2013 117 Obata

Katsura

Mizushima

Yamanaka

Kobayashi

Dai

. TRPA1 induced in sensory neurons contributes to cold hyperalgesia after inflammation and nerve injury. J Clin Invest (2005) 115(9):2393–401. doi: 10.1172/JCI25437 118 Pan

Thapa

Baldissera

Jr. Argunhan

Aubdool

Brain

. Relevance of TRPA1 and TRPM8 channels as vascular sensors of cold in the cutaneous microvasculature. Pflugers Arch (2018) 470(5):779–86. doi: 10.1007/s00424-017-2085-9 119 Lippoldt

Ongun

Kusaka

McKemy

. Inflammatory and neuropathic cold allodynia are selectively mediated by the neurotrophic factor receptor GFRalpha3. Proc Natl Acad Sci U.S.A. (2016) 113(16):4506–11. doi: 10.1073/pnas.1603294113 120 Lippoldt

Elmes

McCoy

Knowlton

McKemy

. Artemin, a glial cell line-derived neurotrophic factor family member, induces TRPM8-dependent cold pain. J Neurosci (2013) 33(30):12543–52. doi: 10.1523/JNEUROSCI.5765-12.2013 121 Yamaki

Chau

Gonzales

McKemy

. Nociceptive afferent phenotyping reveals that transient receptor potential ankyrin 1 promotes cold pain through neurogenic inflammation upstream of the neurotrophic factor receptor GFRα3 and the menthol receptor transient receptor potential melastatin 8. Pain (2021) 162(2):609–18. doi: 10.1097/j.pain.0000000000002043 122 Schaible

. Nociceptive neurons detect cytokines in arthritis. Arthritis Res Ther (2014) 16(5):470. doi: 10.1186/s13075-014-0470-8 123 Aghazadeh Tabrizi

Baraldi

Gessi

Merighi

Borea

. Medicinal chemistry, pharmacology, and clinical implications of TRPV1 receptor antagonists. Med Res Rev (2017) 37(4):936–83. doi: 10.1002/med.21427 124 Kanai

Hara

Imai

Sakakibara

. Differential involvement of TRPV1 receptors at the central and peripheral nerves in CFA-induced mechanical and thermal hyperalgesia. J Pharm Pharmacol (2007) 59(5):733–8. doi: 10.1211/jpp.59.5.0015 125 Vellani

Mapplebeck

Moriondo

Davis

McNaughton

. Protein kinase c activation potentiates gating of the vanilloid receptor VR1 by capsaicin, protons, heat and anandamide. J Physiol (2001) 534(Pt 3):813–25. doi: 10.1111/j.1469-7793.2001.00813.x 126 Yu

Yang

Luo

Liu

Han

Xing

. The role of TRPV1 in different subtypes of dorsal root ganglion neurons in rat chronic inflammatory nociception induced by complete freund's adjuvant. Mol Pain (2008) 4:61. doi: 10.1186/1744-8069-4-61 127 Amaya

Oh-hashi

Naruse

Iijima

Ueda

Shimosato

. Local inflammation increases vanilloid receptor 1 expression within distinct subgroups of DRG neurons. Brain Res (2003) 963(1-2):190–6. doi: 10.1016/s0006-8993(02)03972-0 128 Carlton

Coggeshall

. Peripheral capsaicin receptors increase in the inflamed rat hindpaw: a possible mechanism for peripheral sensitization. Neurosci Lett (2001) 310(1):53–6. doi: 10.1016/s0304-3940(01)02093-6 129 Roskoski

Jr. . Src kinase regulation by phosphorylation and dephosphorylation. Biochem Biophys Res Commun (2005) 331(1):1–14. doi: 10.1016/j.bbrc.2005.03.012 130 Yen

Hsieh

Huang

Lin

. Distal electroacupuncture at the LI4 acupoint reduces CFA-induced inflammatory pain via the brain TRPV1 signaling pathway. Int J Mol Sci (2019) 20(18):4471. doi: 10.3390/ijms20184471 131 Liu

Yang

Wang

. Phosphorylation of TRPV1 by cyclin-dependent kinase 5 promotes TRPV1 surface localization, leading to inflammatory thermal hyperalgesia. Exp Neurol (2015) 273:253–62. doi: 10.1016/j.expneurol.2015.09.005 132 Shin

Itson-Zoske

Cai

Qiu

Pan

Stucky

. Satellite glial cells in sensory ganglia express functional transient receptor potential ankyrin 1 that is sensitized in neuropathic and inflammatory pain. Mol Pain (2020) 16:1744806920925425. doi: 10.1177/1744806920925425 133 Fernandes

Russell

Spina

McDougall

Graepel

Gentry

. A distinct role for transient receptor potential ankyrin 1, in addition to transient receptor potential vanilloid 1, in tumor necrosis factor α-induced inflammatory hyperalgesia and freund's complete adjuvant-induced monarthritis. Arthritis Rheum (2011) 63(3):819–29. doi: 10.1002/art.30150 134 Kobayashi

Fukuoka

Obata

Yamanaka

Dai

Tokunaga

. Distinct expression of TRPM8, TRPA1, and TRPV1 mRNAs in rat primary afferent neurons with adelta/c-fibers and colocalization with trk receptors. J Comp Neurol (2005) 493(4):596–606. doi: 10.1002/cne.20794 135 Huang

Chen

Pan

. Endogenous transient receptor potential ankyrin 1 and vanilloid 1 activity potentiates glutamatergic input to spinal lamina i neurons in inflammatory pain. J Neurochem (2019) 149(3):381–98. doi: 10.1111/jnc.14677 136 Weng

Patel

Jeske

Bierbower

Zou

Tiwari

. Tmem100 is a regulator of TRPA1-TRPV1 complex and contributes to persistent pain. Neuron (2015) 85(4):833–46. doi: 10.1016/j.neuron.2014.12.065 137 Patil

Salas

Bialuhin

Boyd

Jeske

Akopian

. Sensitization of small-diameter sensory neurons is controlled by TRPV1 and TRPA1 association. FASEB J (2020) 34(1):287–302. doi: 10.1096/fj.201902026R 138 Mailhot

Christin

Tessandier

Sotoudeh

Bretheau

Turmel

. Neuronal interleukin-1 receptors mediate pain in chronic inflammatory diseases. J Exp Med (2020) 217(9):e20191430. doi: 10.1084/jem.20191430 139 Ebbinghaus

Uhlig

Richter

von Banchet

Gajda

Brauer

. The role of interleukin-1beta in arthritic pain: Main involvement in thermal, but not mechanical, hyperalgesia in rat antigen-induced arthritis. Arthritis Rheum (2012) 64(12):3897–907. doi: 10.1002/art.34675 140 Ibi

Matsuno

Shiba

Katsuyama

Iwata

Kakehi

. Reactive oxygen species derived from NOX1/NADPH oxidase enhance inflammatory pain. J Neurosci (2008) 28(38):9486–94. doi: 10.1523/jneurosci.1857-08.2008 141 Westlund

Kochukov

McNearney

. Impact of central and peripheral TRPV1 and ROS levels on proinflammatory mediators and nociceptive behavior. Mol Pain (2010) 6:46. doi: 10.1186/1744-8069-6-46 142 Ding

Jiang

Sun

Zhu

. Advanced oxidation protein products sensitized the transient receptor potential vanilloid 1 via NADPH oxidase 1 and 4 to cause mechanical hyperalgesia. Redox Biol (2016) 10:1–11. doi: 10.1016/j.redox.2016.09.004 143 von Banchet

Richter

Huckel

Rose

Brauer

Schaible

. Fibroblast-like synovial cells from normal and inflamed knee joints differently affect the expression of pain-related receptors in sensory neurones: A co-culture study. Arthritis Res Ther (2007) 9(1):R6. doi: 10.1186/ar2112 144 Pereira

Mendes

Pereira

Muniz

Colares

Monteiro

. Transient receptor potential ankyrin 1 channel expression on peripheral blood leukocytes from rheumatoid arthritic patients and correlation with pain and disability. Front Pharmacol (2017) 8:53. doi: 10.3389/fphar.2017.00053 145 Jiang

Shen

Chen

Liu

Wang

Xie

. Nociceptive neuronal fc-gamma receptor i is involved in IgG immune complex induced pain in the rat. Brain Behav Immun (2017) 62:351–61. doi: 10.1016/j.bbi.2017.03.001 146 Qu

Pan

Zhang

LaMotte

. Transient receptor potential canonical 3 (TRPC3) is required for IgG immune complex-induced excitation of the rat dorsal root ganglion neurons. J Neurosci (2012) 32(28):9554–62. doi: 10.1523/JNEUROSCI.6355-11.2012 147 Sadler

Moehring

Shiers

Laskowski

Mikesell

Plautz

. Transient receptor potential canonical 5 mediates inflammatory mechanical and spontaneous pain in mice. Sci Transl Med (2021) 13(595):eabd7702. doi: 10.1126/scitranslmed.abd7702 148 Alawi

Russell

Aubdool

Srivastava

Riffo-Vasquez

Baldissera

L C.OMMAJ.R.X.X.X

. Transient receptor potential canonical 5 (TRPC5) protects against pain and vascular inflammation in arthritis and joint inflammation. Ann Rheum Dis (2017) 76(1):252–60. doi: 10.1136/annrheumdis-2015-208886 149 Zhao

Lieu

Barlow

Sostegni

Haerteis

Korbmacher

. Neutrophil elastase activates protease-activated receptor-2 (PAR2) and transient receptor potential vanilloid 4 (TRPV4) to cause inflammation and pain. J Biol Chem (2015) 290(22):13875–87. doi: 10.1074/jbc.M115.642736 150 Segond von Banchet

Boettger

König

Iwakura

Bräuer

Schaible

. Neuronal IL-17 receptor upregulates TRPV4 but not TRPV1 receptors in DRG neurons and mediates mechanical but not thermal hyperalgesia. Mol Cell Neurosci (2013) 52:152–60. doi: 10.1016/j.mcn.2012.11.006 151 Oehler

Kistner

Martin

Schiller

Mayer

Mohammadi

. Inflammatory pain control by blocking oxidized phospholipid-mediated TRP channel activation. Sci Rep (2017) 7(1):5447. doi: 10.1038/s41598-017-05348-3 152 Yin

Gao

Tao

Chen

Ding

. Paeoniflorin relieves LPS-induced inflammatory pain in mice by inhibiting NLRP3 inflammasome activation via transient receptor potential vanilloid 1. J Leukoc Biol (2020) 108(1):229–41. doi: 10.1002/JLB.3MA0220-355R 153 Fattori

Zaninelli

Ferraz

Brasil-Silva

Borghi

Cunha

. Maresin 2 is an analgesic specialized pro-resolution lipid mediator in mice by inhibiting neutrophil and monocyte recruitment, nociceptor neuron TRPV1 and TRPA1 activation, and CGRP release. Neuropharmacology (2022) 216:109189. doi: 10.1016/j.neuropharm.2022.109189 154 Okubo

Yamanaka

Kobayashi

Fukuoka

Dai

Noguchi

. Expression of leukotriene receptors in the rat dorsal root ganglion and the effects on pain behaviors. Mol Pain (2010) 6:57. doi: 10.1186/1744-8069-6-57 155 Keeble

Russell

Curtis

Starr

Pinter

Brain

. Involvement of transient receptor potential vanilloid 1 in the vascular and hyperalgesic components of joint inflammation. Arthritis Rheum (2005) 52(10):3248–56. doi: 10.1002/art.21297 156 Schaible

von Banchet

Boettger

Brauer

Gajda

Richter

. The role of proinflammatory cytokines in the generation and maintenance of joint pain. Ann N Y Acad Sci (2010) 1193:60–9. doi: 10.1111/j.1749-6632.2009.05301.x 157 Fernandes

Russell

Spina

McDougall

Graepel

Gentry

. A distinct role for transient receptor potential ankyrin 1, in addition to transient receptor potential vanilloid 1, in tumor necrosis factor alpha-induced inflammatory hyperalgesia and freund's complete adjuvant-induced monarthritis. Arthritis Rheum (2011) 63(3):819–29. doi: 10.1002/art.30150 158 Ishida

Kawamata

Tanaka

Shindo

Kawamata

. Calcitonin gene-related peptide is involved in inflammatory pain but not in postoperative pain. Anesthesiology (2014) 121(5):1068–79. doi: 10.1097/aln.0000000000000364 159 Fattori

Pinho-Ribeiro

Staurengo-Ferrari

Borghi

Rossaneis

Casagrande

. The specialised pro-resolving lipid mediator maresin 1 reduces inflammatory pain with a long-lasting analgesic effect. Br J Pharmacol (2019) 176(11):1728–44. doi: 10.1111/bph.14647 160 Nieto

Clark

Grist

Chapman

Malcangio

. Calcitonin gene-related peptide-expressing sensory neurons and spinal microglial reactivity contribute to pain states in collagen-induced arthritis. Arthritis Rheumatol (2015) 67(6):1668–77. doi: 10.1002/art.39082 161 Nakanishi

Hata

Nagayama

Sakurai

Nishisho

Wakabayashi

. Acid activation of Trpv1 leads to an up-regulation of calcitonin gene-related peptide expression in dorsal root ganglion neurons via the CaMK-CREB cascade: A potential mechanism of inflammatory pain. Mol Biol Cell (2010) 21(15):2568–77. doi: 10.1091/mbc.E10-01-0049 162 Hernanz

Medina

de Miguel

Martín-Mola

. Effect of calcitonin gene-related peptide, neuropeptide y, substance p, and vasoactive intestinal peptide on interleukin-1beta, interleukin-6 and tumor necrosis factor-alpha production by peripheral whole blood cells from rheumatoid arthritis and osteoarthritis patients. Regul Pept (2003) 115(1):19–24. doi: 10.1016/s0167-0115(03)00127-7 163 Raap

Justen

Miller

Cutolo

Scholmerich

Straub

. Neurotransmitter modulation of interleukin 6 (IL-6) and IL-8 secretion of synovial fibroblasts in patients with rheumatoid arthritis compared to osteoarthritis. J Rheumatol (2000) 27(11):2558–65. 164 Terenzi

Romano

Manetti

Peruzzi

Nacci

Matucci-Cerinic

. Neuropeptides activate TRPV1 in rheumatoid arthritis fibroblast-like synoviocytes and foster IL-6 and IL-8 production. Ann Rheum Dis (2013) 72(6):1107–9. doi: 10.1136/annrheumdis-2012-202846 165 Clifford

Simpson

Brown

Moyle

Brew

Conway

. A randomized, double-blind, controlled study of NGX-4010, a capsaicin 8% dermal patch, for the treatment of painful HIV-associated distal sensory polyneuropathy. J Acquir Immune Defic Syndr (2012) 59(2):126–33. doi: 10.1097/QAI.0b013e31823e31f7 166 Schnitzer

Pelletier

Haselwood

Ellison

Ervin

Gordon

. Civamide cream 0.075% in patients with osteoarthritis of the knee: a 12-week randomized controlled clinical trial with a longterm extension. J Rheumatol (2012) 39(3):610–20. doi: 10.3899/jrheum.110192 167 Gavva

Treanor

Garami

Fang

Surapaneni

Akrami

. Pharmacological blockade of the vanilloid receptor TRPV1 elicits marked hyperthermia in humans. Pain (2008) 136(1-2):202–10. doi: 10.1016/j.pain.2008.01.024 168 Reilly

McDonald

Puttfarcken

Joshi

Lewis

Pai

. Pharmacology of modality-specific transient receptor potential vanilloid-1 antagonists that do not alter body temperature. J Pharmacol Exp Ther (2012) 342(2):416–28. doi: 10.1124/jpet.111.190314 169 Souza Monteiro de Araujo

Nassini

Geppetti

De Logu

. TRPA1 as a therapeutic target for nociceptive pain. Expert Opin Ther Targets (2020) 24(10):997–1008. doi: 10.1080/14728222.2020.1815191 170 Zhou

Luo

Liu

Qin

. Neurotoxins acting at synaptic sites: A brief review on mechanisms and clinical applications. Toxins (Basel) (2022) 15(1):18. doi: 10.3390/toxins15010018 171 Fan

Chu

Wang

Shi

. Botulinum toxin type a reduces TRPV1 expression in the dorsal root ganglion in rats with adjuvant-arthritis pain. Toxicon (2017) 133:116–22. doi: 10.1016/j.toxicon.2017.05.001 172 Blanshan

Krug

. The use of botulinum toxin for the treatment of chronic joint pain: Clinical and experimental evidence. Toxins (Basel) (2020) 12(5):314. doi: 10.3390/toxins12050314 173 Sun

Yin

Cao

Luo

Zhang

. Anti-nociceptive effects of tanshinone IIA (TIIA) in a rat model of complete freund's adjuvant (CFA)-induced inflammatory pain. Brain Res Bull (2012) 88(6):581–8. doi: 10.1016/j.brainresbull.2012.06.002 174 Ruan

Ling

Cheng

Tang

. Paeoniflorin alleviates CFA-induced inflammatory pain by inhibiting TRPV1 and succinate/SUCNR1-HIF-1alpha/NLPR3 pathway. Int Immunopharmacol (2021) 101(Pt B):108364. doi: 10.1016/j.intimp.2021.108364 175 Montrucchio

Cordova

Santos

. Plant derived aporphinic alkaloid s-(+)-dicentrine induces antinociceptive effect in both acute and chronic inflammatory pain models: evidence for a role of TRPA1 channels. PloS One (2013) 8(7):e67730. doi: 10.1371/journal.pone.0067730 176 Inprasit

Lin

. TRPV1 responses in the cerebellum lobules v, VIa and VII using electroacupuncture treatment for inflammatory hyperalgesia in murine model. Int J Mol Sci (2020) 21(9):3312. doi: 10.3390/ijms21093312 177 Xin

Yang

Shi

Wang

. Distinct roles of ASIC3 and TRPV1 receptors in electroacupuncture-induced segmental and systemic analgesia. Front Med (2016) 10(4):465–72. doi: 10.1007/s11684-016-0482-7