The immunopathogenesis of RA spans decades, with T-cell dysregulation found in the asymptomatic autoimmune abnormal phase of RA (a period of autoantibody production to post-translational modified proteins), the acute synovitis phase, and the chronic destructive synovitis phase (35). Aberrant T cell differentiation is fundamental in promoting the remodelling of the immune system prior to the disease (36). Another way in which pathogenic T cells drive chronic inflammation is associated with the formation of organised lymphoid structures (37), which provide strength and persistence to inflammatory immunity. Moreover, synovial T cells are an important source of inflammatory factors such as IFN-γ (38), IL-17 (39), and TNF-α (40), and are a key bridge between cytokines and adaptive immune abnormalities and tissue remodelling.

Expression of TRPV1 was detected in human primary T cells, Jurkat T cell line, and mouse spleen T cells (29, 41–43). TRPV1 is positioned on the T cell plasma membrane and is one of the pivotal components of the T cell receptor (TCR) signalling cascade. TRPV1 activation and function can be regulated through TCR-induced signalling pathways (44). TRPV1 is rapidly recruited to the TCR cluster in an Src-dependent manner after TCR stimulation (42), which is an important way to increase Ca²⁺ concentration in CD4⁺ T cells. Resiniferatoxin, a specific agonist of TRPV1, leads to increased Ca²⁺ influx in T cells (29). Elevated intracellular Ca²⁺ is imperative for promoting T cell functions, such as activation, proliferation, differentiation and exerting effector functions (45). Genetic deletion or pharmacological inhibition of TRPV1 can attenuate the pro-inflammatory phenotype of CD4⁺ T cells (42, 46). Knockdown of TRPV1 in human primary CD4⁺ T cells reduces the expression of CD25 and shared epitope-positive HLA-DR alleles and diminishes the generation of anti-citrullinated protein antibodies (ACPA) in RA patients (42).In addition, TRPV1 antagonists can reduce the production of inflammatory factors. Compared to wild-type(WT), TRPV1^-/-CD4⁺ T cells secreted fewer cytokines (IFN-γ, IL-17A, IL-2, IL-10, IL-4 and TNF) following anti-CD3 + 28 stimulation, and their reduced cytokine production may be due to a decrease in TCR-induced the TRPV1 channel-mediated Ca²⁺ influx (42). Although the role of TRPV1 and T cell activation in the pathogenesis of RA remains to be clarified, the role of TRPV1-mediated Ca²⁺ influx in T cell proliferation and activation is undisputed. Considering the important pathological role of T-cell activation in RA, it can be inferred that targeting and regulating TRPV1 to restore normal physiological functions of T-cells holds great promise in the treatment of RA.

TRPV1 has been reported to be involved in macrophage-related immune mechanisms (47). Abnormal activation of pro-inflammatory macrophages in synovial tissue is detected in early RA (48, 49). When pro-inflammatory macrophage M1 are over-polarized, the secretion of cytokines such as IL-1β, IL-6 and TNF-α increases in vivo ( 48, 50), inducing inflammation production and leading to high disease activity in RA. TRPV1 hyperactivation promotes M1-type pro-inflammatory macrophage activation by altering macrophage status (51). An imbalance in the M1/M2 ratio of articular synovial macrophages is a distinctive feature of the acute inflammatory phase of RA (52, 53). Not only are macrophages themselves a source of inflammation, but they are also associated with the activation of T cells. Macrophages can present non-self antigens to nascent T cells, by releasing cytokines and growth factors that elicit Th1 or Th2-mediated immune responses and modulate inflammation in vivo (54). Pretreatment of mouse macrophages with TRPV1 inhibitor AMG9810 or CPZ significantly inhibited the expression of pro-inflammatory cytokines IL-6, IL-1β and IL-18, as well as cyclooxygenase 2 (COX-2) (55). An opposite result has been shown, with TRPV1 agonist treatment significantly reducing macrophage polarisation, attenuating synovial inflammation and minimising cartilage destruction and bone formation (31).

Macrophage polarization derangement is a key mechanism of bone destruction in RA. The degree of synovial macrophage infiltration is closely related to the degree of joint erosion (49). An interesting subpopulation of macrophages called arthritis-associated osteoclast macrophages, has been discovered in the synovial fluid and tissues of RA patients (56). These macrophages are characterised by a high osteoclastogenic potential (56). TRPV1 activation facilitates the mobilization of M1-type pro-inflammatory macrophages. Inflammatory macrophages are involved in joint surface erosion through the production and release of matrix metalloproteinases (57). M1-type macrophages are intimately associated with osteoblasts. During the erosive phase of the disease, chemokine CCL21 enhances RA osteoclastogenesis by driving Th17 polarization through M1-type macrophages. Thus, CCL21-mediated differentiation of M1-type macrophages linked to Th17 cells extends joint inflammation into bone erosion (57). The macrophage-osteoclast axis may be an important mechanism of bone destruction in RA (58). TRPV1 can reduce inflammation and osteoclast production by regulating the M1/M2 macrophage imbalance and is expected to be a new therapeutic target for RA.

TRPV1 and macrophages are not limited to their involvement in inflammation and bone destruction but are also associated with mechanical pain and burning sensations. IL-23/IL-17A/TRPV1 axis activation contributes to macrophage-sensory neuron crosstalk, creating mechanical pain (59). Radiofrequency irradiation lowers TRPV1 activation, diminishes neuropeptide expression, attenuates neuropeptide-induced macrophage activation, and ultimately reduces inflammatory factor expression and burning pain in vitro models (60). The mechanism by which TRPV1 is involved in macrophages to regulate inflammation and bone destruction in the body has been well clarified. Yet, the mechanism of TRPV1-induced neuropeptide expression and macrophage activation in RA patients with burning joint pain remains to be further elucidated.

TRPV1 has been proven to be expressed in mouse and human DCs at the protein and gene levels (28, 61, 62). The TRPV1 agonist CAP exhibits a dose-dependent effect of inducing DCs differentiation and prompting DCs activation. TRPV1 binds to immature DCs and promotes DCs maturation through antigen presentation and upregulation of co-stimulatory molecules (61). Substantial amounts of DCs are recruited in the synovial fluid and tissues of RA patients and are integral in the pathogenesis of RA (63, 64). DCs specialized antigen-presenting cells bridge innate and adaptive immunity (65), drive Th1/Th2 imbalance, activate B cells and follicular helper T cells (Tfh) (66, 67), and stimulate the body to generate high levels of autoantibodies, resulting in an inflammatory response.

TRPV1 regulates DCs function, and sustained opening of the TRPV1 channel promotes activation of calcium-regulated neuro phosphatase/NFATc2 signalling in DCs, impairing Ca²⁺ homeostasis in DCs, enhancing Th17 cell differentiation, inducing cytokine secretion and strengthening susceptibility to inflammatory factors (68). Excessive secretion of chemokines by synovial DCs in RA patients and recruitment of immune cells with pro-inflammatory functions, such as macrophages and neutrophils (69, 70). Overexpression of NF-κB was found in RA synovial DCs, causing upregulation of nuclear RelB, a binding protein for NF-κB, and promoting inflammation. Similar manifestations were found in inflammatory bowel disease (IBD) mice, where activation of TRPV1 promoted DCs recruitment and activation compared to TRPV1^-/-, exacerbating the colitis manifestations of the model (68).

However, studies have suggested the opposite, that the failure of CAP to induce changes in intracellular Ca²⁺ or membrane currents in DCs does not support the expression of the TRPV1 channel in DCs (71). The reason for this may be that although CAP can agonize the TRPV1 channel, numerous studies have shown that TRPV1 receptors may not be the only target of CAP. The specific role of TRPV1 in the regulation of DCs by CAP remains unclear. Although several studies have supported the idea that TRPV1 regulates DCs and influences the inflammatory response of the body. Further validation at the cellular level using TRPV1^-/- or agonists and inhibitors to elucidate the mechanisms of TRPV1 regulation of inflammation in DCs and RA patients is an important next step in the research.

Overproduction of IL-1β causes vasodilation, promotes granulocyte recruitment to inflamed tissues and induces prostaglandin (PG) expression, contributing to acute joint inflammation and pain (72, 73). IL-1β also stimulates osteoclast formation through the induction of osteoclast genesis in regulatory T-cells (Tregs), contributing to bone erosion and joint function reduction (74, 75). TRPV1 is an integral pathway for IL-1β release. Studies have shown that injurious TRPV1⁺ axons co-express IL-1R1 and are tightly correlated with infiltrating IL-1β⁺ cells. In both mouse and human models, IL-1R1 was found to be highly expressed through a subpopulation of TRPV1⁺ dorsal root ganglion neurons (76). TRPV1 channel induces Ca²⁺ influx in the extracellular medium and increases cytosolic Ca²⁺ concentration, possibly through increased nuclear NF-κB phosphorylation leading to increased IL-1β release (77). Pretreatment with TRPV1 antagonist significantly eliminates IL-1β-induced pain (78). No elevation of IL-1β was seen in the TRPV1 KO mouse model compared to WT mice (79, 80). Inhibition of IL-1 secretion through modulation of the TRPV1 channel to attenuate joint inflammation and pain merits further exploration.

Elevated levels of synovial TRPV1 in RA patients are accompanied by abnormal secretion of IL-6 (81). TRPV1-induced IL-6 secretion plays an instrumental role in patients’ pain, inflammation, and joint destruction. Activation of TRPV1 operates as an inducer of inflammatory signalling and collaborates with neuropeptides to augment the production of the cytokine IL-6. However, this synergistic mechanism does not affect healthy synovial cells, and only inflammation-initiated cells can generate IL-6 through the activation of the TRPV1 channel (81). IL-6 plays a checkpoint role in the differentiation pathway of naive T cells to pro-inflammatory Th17 cells or Tregs (82). IL-6 acts as a chemoreceptor for monocytes at the site of inflammation, affecting signalling molecules such as Toll-like receptors (TLR) and promoting angiogenesis (83). IL-6 mediates the induction of bone resorption by TNF-α and IL-1. IL-6 stimulates the release of osteoblast nuclear factor-κB receptor activator (RANK) ligand (RANKL) and destroys bone via the RANK/RANKL/osteoprotegerin (OPG) pathway (84). The simultaneous destruction of the vascular opacification leads to irreversible damage to the joint (85). The use of TRPV1 inhibitors reduces the body’s IL-6 levels (86). TRPV1 KO mice secreted less IL-6 compared to WT mice (87). Thus, TRPV1-induced IL-6 secretion has an essential role in inflammatory, neurogenic and pressure pain in the body.

TRPV1 has a regulatory effect on IL-8. It was revealed that activation of TRPV1 often induces IL-8 formation. Elevated levels of TRPV1 in the hyperosmotic state and response to dramatic temperature changes stimulate MAPK and NF-κB activation and mediate an increase in the chemokine IL-8 (88). IL-8 is a key chemokine that promotes neutrophil migration (89). IL-8 activates neutrophils, stimulates neutrophil extracellular trap formation, promotes their degranulation, produces respiratory bursts, releases superoxide and lysosomal enzymes, and facilitates the activation and recruitment of neutrophils at sites of inflammation (90). IL-8 also has the capability to appeal to and activate monocytes, and large quantities of inflammatory cells infiltrate the interstitial matrix of articular cartilage and bone (91, 92). IL-8 can also stimulate angiogenesis, resulting in the formation of RA vascular opacities (91). The use of the TRPV1 agonist CAP confirms the regulatory function of TRPV1 on IL-8 (93). Reduced local pH is an essential pathological feature of RA. Acidic conditions can contribute to elevated IL-8 mRNA expression (94). Intriguingly, the selective TRPV1 antagonist 5’-iodoresiniferatoxin reduced the production of IL-8 under acidic conditions and attenuated the inflammatory state of the organism (95).

IL-8 also has osteoclastogenic activity. IL-8 promotes the formation of pro-osteoblast-like cells (OCL) in an environment with anti-RANKL antibodies, demonstrating that IL-8 may compensate for RANKL function during the induction of OCL in a low-RANKL environment and accelerate the process of RA bone destruction (96). TRPV1 may have an impact on bone destruction in RA patients by mediating IL-8 secretion.

It was revealed that TRPV1⁺ injury receptors are closely related to the production of IL-17. IL-17 can induce aggregation of neutrophils and monocytes in the circulatory system, activates a series of inflammatory cascades and plays a fundamental role in RA (97). TRPV1 activates the IL-23/IL-17 axis, which mediates inflammation through macrophage-neuron crosstalk drive (98). TRPV1 KO abrogates IL-23/IL-17 axis-induced inflammation. At the same time, IL-17, in turn, acts on TRPV1, the two interact through neural-immune interactions, contributing to the body’s mechanical pain (59). The use of TRPV1 agonists CAP, SA13353 [1-[2-(1-adamantyl)ethyl]-1-pentyl-3-[3-(4-pyridyl)propyl]urea] also demonstrated anti-inflammatory effects. CAP administration inhibited the expression of the IL-23/IL-17 pathway in psoriasis models, alleviated the microscopic appearance of lesions and reduced the secretion of various cytokines (99). SA13353 suppresses the recruitment and production of IL-17-producing cells and decreases inflammation in the body (100). TRPV1 KO confirmed its induction of IL-17 production causing inflammation in the body, but its agonist use also reduced inflammation in the body, suggesting that both agonists and inhibitors of TRPV1 can exert anti-inflammatory effects via IL-17 secretion, and the mechanism of action requires further exploration.

TNF-α induces inflammation and promotes osteoclastogenesis, which is critical in the pathogenesis of RA. TNF-α inhibitors are widely used to treat RA and can mitigate RA symptoms by preventing the pro-inflammatory signalling pathway mediated by TNF receptor 1 (TNFR1) (101). TRPV1 promotes TNF-α production and is also induced by TNF-α, both of which exert synergistic inflammatory effects. Pretreatment of isolated rat vagus nerves with TNF-α enhances the response of sensory neurons to TRPV1 agonists and mediates increased TRPV1 expression and Ca²⁺ influx (102). In TNF-α overexpressing mice, elevated TRPV1 levels and elevated Ca²⁺ influx levels were demonstrated, indicating that TNF-α overexpression induced TRPV1 sensitization (103). TNF-α-triggered thermal and mechanical hypersensitivity in the body is mediated by TRPV1 signalling downstream of TNFR1 receptor activation, respectively, and sensitization of injury receptors is dependent on TNFR1 expression (104).

Also, TRPV1 mediates the production of TNF-α. Paeoniflorin inhibits TRPV1 expression in foot pad tissue samples, suppresses inflammatory cytokine TNF-α production and ameliorates inflammation and pain in mice in an LPS-induced acute pain model (105). However, the analgesic effect of paeoniflorin can be significantly reversed by CAP, suggesting that TRPV1 channel activation mediates the release of inflammatory factors such as TNF-α, leading to inflammatory pain.

TRPV1 and TNF-α exhibit a close reciprocal relationship and their mutual regulatory role cannot be ignored. Of interest is that in two studies, TRPV1 agonists showed a dual anti-inflammatory and pro-inflammatory effect and inflammatory cytokines such as TNF-α also showed a paradoxical elevation and inhibition (106, 107). The mechanism of TRPV1’s role in this requires further clarification. It is undeniable that TRPV1 is tightly associated with TNF-α, and blocking the reciprocal relationship may reduce the inflammatory response in RA patients, and may also delay bone destruction, diminish disability and improve the quality of patient survival.

Overproduction of IFN-γ in RA patients drives the recruitment of synovial neutrophils, which is accompanied by high disease activity and leads to persistent inflammation (108, 109). TRPV1 mediates IFN-γ production. In a model of inflammation induction, both inflammatory genes IFN-γ and TRPV1 channel were upregulated, and TRPV1 agonists systematically increased T cell counts, enhanced CD8⁺ T cell recruitment and induced overproduction of IFN-γ in healthy mice (110, 111). Nevertheless, a novel TRPV1 agonist, SA13353, attenuated IFN-γ cytokine levels, possibly associated with the desensitization of TRPV1 (100). Although TRPV1 channel opening correlates with IFN-γ secretion, there is still a lack of strong evidence to support this. Whether TRPV1 KO affects the secretion of IFN-γ and thus the development of RA still needs to be further explored.

Activation of the TRPV1 channel is known to cause inflammation in vivo, but there is growing evidence that it has anti-inflammatory effects. TRPV1 is expressed in a variety of immune cell subpopulations, and activation of the channel is closely synergistic with the release of regulatory proteins, and inflammatory factors. These synergistic relationships may influence the final outcome of TRPV1 activation.