Formyl peptide receptors (FPRs) (mFPRs in mice) are a small group of G protein-coupled receptors (GPCRs) with seven transmembrane domains. FPRs were initially identified as binding to and activated by N-formyl peptide, which is released from the damaged mitochondria of skin bacteria during tissue injury (Hilger et al., 2018). FPRs transduce chemotactic signals in phagocytes that react to tissue injury-associated chemotactic molecular patterns, which mediate cell adhesion, directed migration, degranulation, and superoxide production, thereby regulating host-defense and inflammatory responses through intracellular calcium mobilization and mitogen-activated protein kinase (MAPK), extracellular-regulated protein kinase (ERK), phosphoinositide-3-kinase (PI3K), protein kinase B (Akt), and p38/MAPK signal transduction pathways (Dorward et al., 2015). Interestingly, FPRs play both anti-inflammatory and pro-inflammatory roles, depending on the ligands type and the inflammatory microenvironment. Increasing attention has been paid to their role in the pathogenesis of both infective and non-infective inflammatory diseases. When FPRs are expressed on leukocytes during bacterial or viral infections, they sense microbe-specific molecular pattern molecules, thereby leading to leukocyte activation and chemotaxis. Additionally, FPRs participate in non-infective inflammation of wound-healing (Liu et al., 2014) and reduce allergic reactions in the airways (de Oliveira et al., 2017), as well as facilitate tumor invasion by regulating tumor-associated inflammation and escape responses (Chen et al., 2017).

Neuroinflammation occurs in the brain and spinal cord, primarily caused by abnormally acute or chronic activation of glial cells. Its intensity and extent varies between the pathogeneses of injury, infection, or stress responses mediated by cytokines, chemokines, and reactive oxygen species (ROS), among secondary messengers (DiSabato et al., 2016). Inflammation causes immune activation, cell death, edema, and tissue damage, which lead to neurological disease. Neuroinflammations regulate neurodegenerative diseases (Alzheimer’s disease), neurological tumors (gliomas, neurilemmas), and cerebrovascular diseases (stroke, carotid stenosis), affecting their occurrence, development and prognosis (DiSabato et al., 2016). The expression and distribution of FPRs in different regions of the brain and spinal cord have been identified (Ho et al., 2018). FPRs in neuronal cells and tissues are significant for the identification of agonists and neural cell expression that trigger multiple intracellular signaling pathways to regulate various pathophysiological conditions (Cussell et al., 2020). The FPR ligands N-formyl-leucine-phenylalanine (fMLF) and serum amyloid A (SAA) exert pro-inflammatory effects, while annexin-1 (AnxA1), lipoxin A4 (LXA4), and resolvin-D1 (RvD1) produce pro-resolving effects. FPRs monitor glial activation (Han et al., 2020), accelerate neural differentiation (Urban et al., 2019), promote axon and dendrite growth (Ho et al., 2018), regulate immune escape of intracranial tumors (Yao et al., 2008), and regulate blood brain barrier (BBB) permeability (Liu H. et al., 2021), thereby affecting the progression of neurological diseases. This review elucidates the recent advances in determining the pluripotent physiological roles of FPRs in the neurological disease microenvironment and proposes several cases that emphasize on the therapeutic potentials of FPRs, especially FPR1 and FPR2, for regulating host defense and fostering innate immunity.

Formyl peptide receptors belong to the seven-transmembrane GPCR family, many of which play important roles in anti-bacterial host defense mechanisms. Their polypeptide chains are composed of extracellular N-terminal domains, intracellular and extracellular loops, and seven transmembrane helices linked to the intracellular C-terminal. The human FPR family comprises FPR1, FPR2, and FPR3, which are myeloid receptors expressed in monocytes/macrophages and neutrophils, and have phagocytic capabilities (Liu H. et al., 2021). Formylated peptides, non-formylated peptides, synthetic small molecules, and eicosanoids from bacteria and mitochondria can be identified by FPRs to govern inflammatory reactions leading to chemotaxis, degranulation, and oxidative burst (Ye et al., 2009; Schepetkin et al., 2014; Weiß and Kretschmer, 2018). Therefore, FPRs are deemed as pattern-recognition receptors as they interact with both pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) (McDonald et al., 2010; Zhang et al., 2010).

The first-identified and shortest formyl peptide with the potential for full agonistic activity is fMLF, which is derived from Escherichia coli. This peptide triggers a variety of biological activities in phagocytes and myelocytes (Marasco et al., 1984). FPRs bind many host-derived non-formyl peptide agonists to regulate pathophysiological processes. Serum amyloid A (SAA) comprises a family of prominent acute-phase proteins, which were the first endogenous peptide agonists identified for FPRs (Su et al., 1999). Recent research shows that SAA exerts type 2 immunity in the respiratory system through the release of IL-33 and induces intestinal epithelial wound closure associated with alterations in the focal adhesion protein p130 CAS localization and ROS induction (Hinrichs et al., 2018; Smole et al., 2020). The pathologies underlying protein misfolding are many, and misfolded proteins are host-derived proteins that induce FPR-activation, particularly FPR2. A familiar amyloidogenic protein associated with an FPR2 agonist is amyloid-β 1-42 (Aβ1-42), a well-documented peptide fragment in patients with Alzheimer’s disease (AD) (Wickstead et al., 2020), and the prion protein fragment PrP (106-126), which interacts with FPRs on astrocytes and microglia and regulates inflammatory process such as calcium mobilization, chemotaxis, and the production of pro-inflammatory cytokines (Le et al., 2001b). AnxA1, LXA4, and RvD1 are regarded as endogenous pro-resolving FPR ligands. AnxA1, also called lipocortin-1, is secreted in response to tissue damage, and its N-terminal peptides, Ac2-26 and Ac9-25, have a concentration-dependent interaction with FPRs (He and Ye, 2017).

An increasing amount of evidence has demonstrated the significant role of AnxA1 in cell proliferation, phagocytosis, apoptosis, and the origination and development of tumors (Foo et al., 2019). LXA4 and RvD1 are host-derived lipid and lipopeptide agonists that impede the activation of FPR2-dependent signaling, including calcium mobilization (He and Ye, 2017). Interestingly, highly phosphorylated FPR3 is localized in small intracellular vesicles, but they are unresponsive to formyl peptides. An acetylated N-terminal fragment of F2L, a human heme-binding protein, and the neuroprotective peptide humanin are characteristic FPR3 agonists. However, the functional role of FPR3 remains unclear (Migeotte et al., 2005; Rabiet et al., 2011).

The binding of AnxX1, LXA4, RvD1 triggers FPRs activation, leading to signaling pathways that regulate inflammatory responses. Although FPR1 and FPR2 differ in specificity and binding properties, their amino acid sequences are 69% homologous, and therefore, both FPRs are probably activated through the same signaling pathways (Ye et al., 2009). The identification of bacteria-chemotactic PAMPs and host tissue-derived chemotactic DAMPs by FPRs leads to an inflammatory cascade reaction. The FPR ligands, fMLF and SAA exert pro-inflammatory effects, while AnxA1, LXA4, and RvD1 produce pro-resolving effects (Dufton and Perretti, 2010; Bozinovski et al., 2013). The inflammatory response mediated by FPR-signaling pathways contains FPRs regulating pro-inflammatory effects by enhancing leukocyte transport and inhibiting neutrophil apoptosis, whereas receptor-mediated anti-inflammatory effects are also inhibited similarly (Chen et al., 2017). The binding of the ligands to FPR1 or FPR2 causes a conformational change, which subsequently activates downstream molecules. The GTPases of the Ras superfamily, such as Ras, Rho, CDC42, and Rac, activate MAPK pathways, ERK1/2, p38, and JUN-N-terminal protein kinase (JNK) (Zhao et al., 2015). Phospholipase Cβ (PLCβ) is activated by another subunit, leading to the release of intracellular calcium from the endoplasmic reticulum, thereby activating PKC, and ROS production (Kwan et al., 2008; Dorward et al., 2015). Furthermore, the subunit also activates PKCs and Akt. These crucial signal transduction pathways contribute to degranulation, chemotaxis, superoxide production, and transcriptional regulation (Dorward et al., 2015). The recognition of chemotactic PAMPs and DAMPs induces the binding of pro-inflammatory or pro-resolving ligands to FPRs, which may trigger or inhibit a series of intracellular kinase pathways that affect the regulation of various cellular functions (Figure 1).

Neuroinflammation refers to inflammation that occurs in both central and peripheral nervous system, which involves the glial cells (Liddelow et al., 2017; Yun et al., 2018) and perivascular macrophages (Liddelow et al., 2017; Yun et al., 2018), and the main role is considered to be microglia (Colonna and Butovsky, 2017; Cable et al., 2020). Neuroinflammation is reportedly a complex process involving the coordination of different groups of glial cells, which act as a double-edged sword in this process, depending on the progression of the disease and the inflammatory microenvironment (Shabab et al., 2017; Yang and Zhou, 2019). The first attempt to visualize in vivo FPRs in mouse brains by positron emission tomography was undertaken by Lacivita et al. (2016). They found that FPRs are expressed in the microglia and mediate the chemotactic activity of Aβ peptides in AD, and they are thus involved in the chronic neuroinflammation process (Lacivita et al., 2016). The FPR mRNA is generally present in all regions of the brain, with higher expression in the brainstem and spinal cord (Ho et al., 2018). The biological significance of FPRs in the nerve cells and tissues has been elucidated through separate inflammatory signaling pathways.

Primarily, microglia cells monitor the physiological environment and act as the first line of defense when the brain suffers various injuries. For acute processes, such as ischemia and trauma, microglia cells maintain homeostasis by controlling the spread of neuroinflammation. Untimely chronic neuroinflammation causes neuronal damage, which is a prominent feature of progressive neurodegenerative diseases (Graeber, 2014; Leszek et al., 2016). The steady-state of the nervous system requires immunity surveillance and a suitable response from the microglia cells and peripheral immune cells via the release of pro-inflammatory cytokines and oxidative stress products (Abushouk et al., 2017). Animal experiments confirmed that the Th2-type cytokine IL-4 markedly inhibited TNF-α induced expression of mFPR2 in microglial cells by attenuating the activation of ERK and p38 MAPK, and that of NF-κB (Iribarren et al., 2005). Stimulation of brain mFPR2 with LXA1 or AnxA1 can inhibit microglial activation, thus diminishing neuroinflammation of several pathological conditions (Stama et al., 2017).

Astrocytes compose the most abundant subtype of neuroglial cells in the brain, and are intimately associated with brain homeostasis in the course of energy acquisition, neurotransmitters metabolism, and neuroinflammation (Dong and Benveniste, 2001). The activation of astrocytes in response to pathological conditions drive from the primary activation of microglia and cytokines such as IL-1 and IL-1β and subsequently release inflammatory cytokines. Reactive astrocytes divide into two phenotypes with strikingly opposite functions. On the one hand, they play potential beneficial role in synapse formation, neuronal development and proper propagation of action potentials (Liddelow and Barres, 2017). On the other hand, it is noteworthy that some pathological components, including oxidative stress, free saturated fatty acids, and lipopolysaccharide, upregulate reactive astrocytes to provoke Aβ-induced neuronal death and synaptic impairment (Sawikr et al., 2017). An increasing body of data has indicated that the FPRs exert their biological effects in neuroinflammation induced by astrocytes. Zhang et al. (2019) has carried out a trial in a mouse model of AD and reported that FPR2 deficiency facilitated activation of astrocytes and prognosis improvement. A previous U87 astrocytoma cell model study showed that the stimulation of FPR2 in vitro increased MAPK activities, which could be abrogated in the presence of an FPR2 antagonist. FPR2-induced ERK and JNK augment the expression of glial fibrillary acidic protein and IL-1α, which are correlated with reactive astrocytosis (Kam et al., 2007).

Several studies demonstrated that FPRs promote neural differentiation. Neural stem cells (NSCs), are used to study neurons and glial cells of stroke, along with the spinal cord, thus contributing to the rapid growth and repair of neural tissues. Activation of MAPK and PI3K/Akt pathways significantly increases NSC differentiation and decreases the number of apoptotic cells (Ishii et al., 2010). Wang et al. (2016) identified that mFPR1 and mFPR2 are expressed in NSCs, and mediate the migration of and promote the differentiation of NSCs to neurons. Further research conducted by this team proved that the self-renewal and neurogenesis of NSCs activated by mFPR2 signaling was regulated through the PI3K/Akt pathway and ROS production (Zhang et al., 2017). Moreover, mice lacking the mFPR1 gene show decreased expression of the second messengers, p38 MAPK and ERK, and reduced NF-κB translocation into the nucleus following traumatic brain injury (TBI) (Fusco et al., 2020). In addition, mFPR1 influences neurogenesis through regulation of the PI3K/Akt pathway (Le Belle et al., 2011; Fusco et al., 2020).

Axonal or Wallerian degeneration is a prominent early feature of most neurodegenerative diseases and nerve injuries. The activation of the Schwann cell (SC) phenotype after nerve injury is associated with inflammatory characteristics and inducing a microenvironment for axon regeneration (Stoll et al., 2002; Rotshenker, 2011; Dubovy et al., 2013, 2014). We speculate FPRs activate SCs, from which SAA originates after nerve injury and induce the cytokine monocyte chemoattractant protein-1 and macrophage inflammatory peptide-1α, which are synthesized from the SCs. The SAA may induce macrophage movement during Wallerian degeneration, which can be blocked by an FPR2-antagonist (Jang et al., 2012). Korimova et al. discovered that mitochondrial DAMPs released from axonal mitochondria modulate the outgrowth of cytoplasmic processes of the RT4 SC process in a dose- and time-dependent manner. Immunofluorescence staining also revealed that mFPR2 exists in the SCs and in the nerves distal to nerve injury (Korimova et al., 2018). In addition, mFPR2 is observed in growth cones, suggesting its involvement in axonal regeneration. Korimova et al. seconded this finding in a subsequent investigation (Korimova and Dubovy, 2020). Another analysis based on a facial nerve injury model corroborated the findings regarding the factors associated with remyelination involved in FPR. AnxA1 acts as the extracellular trigger for SC proliferation and migration, and activates FPR2 and the downstream adenosine 5′-monophosphate (AMP)-activated protein kinase (AMPK) inflammatory signaling cascade. AMPK phosphorylation induced by insulin-like growth factor-1 improves the mitochondrial function to drive axonal outgrowth, therefore promoting the SC proliferation and nerve regeneration (Xia et al., 2020).

The BBB is the primary communication channel between systemic circulation and that in the brain, and its function is to prevent the destructive effects on the central nervous system (CNS) due to problems maintaining peripheral homeostasis during inflammation and metabolic diseases. Tight junctions (TJs) invade toxic substances and stop cells from passing through the vascular wall via the paracellular and transcellular pathways (Carman et al., 2007). Since the BBB is highly vulnerable to metabolic toxins, enhanced BBB-permeability can lead to edema, disruption of ionic homeostasis, and immune infiltration, causing neuronal dysregulation and depriving the BBB of its function (Daneman and Prat, 2015). The FPRs agonist AnxA1 is reportedly a critical component of the normal BBB. Exogenous human recombinant AnxA1 inhibited BBB disruption and intrusion of systemic inflammation into the brain through the Ras homolog gene family member A (RhoA) and rho-associated coiled-coil kinase (ROCK) inhibition, thereby improving functional outcomes in controlled cortical impact mice. The RhoA and the major downstream effector ROCK can enhance paracellular permeability by initiating the signal transduction pathway leading to the destabilization of the actin cytoskeleton during cell adhesion, migration, contraction, and proliferation (Terry et al., 2010). AnxA1 knockout mice exhibited a higher degree of neutrophil exosmosis associated with RhoA activity (Terry et al., 2010). The recombinant AnxA1 negatively regulated the RhoA/ROCK pathway and stabilized endothelial actin proteins and TJs; p38/MAPK phosphorylation increased significantly in response to cerebral inflammation-induced BBB disruption, whereas LXA4 treatment reduces inflammation through the FPR2/p38/MAPK signaling pathway (Guo et al., 2016). Thus, the signal cascade triggered by the combination of AnxA1 and FPR2 may be a target for the treatment of BBB dysfunction (Figure 2).

Of note, FPR1 and its variants FPR like 1 (FPRL1) serve as a critical component in angiogenesis, cell proliferation, and signaling pathways of neuroinflammation (Cattaneo et al., 2010). Pharmacological studies have recently confirmed that FPR1 exerted efficient effects on resisting neuroinflammation by restraining proinflammatory mediators, such as TNF-α and IL-1β, otherwise inducing IL-1RA and IL-10 expression (Calvello et al., 2021). FPR1 is expressed in neuronal tissues. Several signaling molecules, such as p38/MAPK, PKC, and PLC are required for FPR1 activation, which triggers NF-κB and STAT3 transcriptional factors. It has been described that FPR1 promotes neuronal differentiation of neural stem cells after TBI (Fusco et al., 2020). In the course of demyelination, FPR1 induces and maintains the glial cell activation thus is deemed as an important part of the innate immune in chronic degenerative diseases such as multiple sclerosis (Bihler et al., 2017). Most recent data showed that FPR1 deficiency alleviated brain edema and improved neurological outcomes in intracerebral hemorrhage (ICH) models (Li et al., 2021). Interestingly, FPRL1 also belongs to GPCRs. Expressed on both astrocytes and microglia, FPRL1 is generally thought to be involved in neuroinflammation. Using U87 astrocytoma cell model, Kwan and his colleagues demonstrated that FPRL1 gained access to promote calcium influx via switching store-operated channels (Kwan et al., 2008). Besides, FPRL1 has been shown to exert positive role in attenuating bacterial meningitis. Braun et al. evidenced that FPRL1 synergies with macrophage receptor with collagenous structure were essentially related in glial cell activation and antimicrobial peptides expression during resistance to meningitis (Braun et al., 2011).

Due to the complexity, diversity, and multicellular process of neuroinflammation, it is firmly associated with a series of neurological diseases. FPRs are responsible for occurrence and prognosis of the disease.

In recent years, much progress has been made in understanding the biological roles played by FPRs in the pathophysiological processes of neurological diseases. The FPR family has dual inflammatory functional properties, including pro-inflammatory and anti-inflammatory functions by triggering or inhibiting a series of GPCR intracellular kinase pathways, the activation of which can stimulate several signal transduction pathways depending on the ligands, its reaction microenvironment, and the cell type involved. It is beneficial to terminate transient inflammation through a proper decomposition process, which usually leads to a neuroprotective effect. Chronic inflammation leads to long-term homeostasis disease, permanent neurotoxicity, or neurodegenerative changes, and becomes the fundamental cause of CNS diseases. Neuroinflammation is central to several neurological diseases, including neurodegenerative diseases, stroke, neurogenic tumors, and SCI. Due to the complex and multifactorial nature of the structure and function within the nervous system, the accuracy and efficacy of therapeutic interventions for these neurological diseases remain unsatisfactory. Rapid developments in recent years have suggested that the specialized pro-resolving mediator, FPR2, acts as a key molecule that mediates the active resolution of inflammation in the CNS (Figure 3). AnxA1, LXA4, and RvD1 are common anti-inflammatory agonists, which bind with FPR2 to reduce the expression and activation of pro-inflammatory composition, govern the transport of immune cells to inflammatory tissues, and restore the integrity of the BBB. Thus, treatment with FPR2-modulation may be effective for neurological diseases. Recent studies are mainly limited to animal experiments, and the specificity of these mechanisms of FPR-mediated inflammation remains unclear. Future research should focus on the concrete and in-depth mechanisms of FPRs in inflammatory diseases of the human nervous system.

JZ, LL, JD, and JH performed the literature review and wrote the manuscript. AS and BT helped with the outline and article modification. All authors read and approved the final manuscript.

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

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