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    • Formyl peptide receptors FPRs are a family

    2022-05-12

    Formyl peptide receptors (FPRs) are a family of surface-expressed, G protein-coupled receptors [7]. The three members, FPR1, FPR2 and FPR3, share significant sequence homology, but have different functional properties [7]. While FPRs are mainly expressed by innate leukocytes, they are also found on other immune and non-immune cells [[7], [8], [9]]. Within the immune system, FPR1 is expressed predominantly on myeloid cells, while FPR2 is also found on B cells, as well as naïve and, to a greater extent, activated/memory T cells [[7], [8], [9], [10], [11]]. FPR2 binds various ligands including Annexin A1 (AnxA1), lipoxin A4 and serum amyloid A (SAA), whereas FPR1 binds AnxA1, cathepsin G, FAM19A4 and formylated bacterial and mitochondrial peptides, resulting in their diverse ligand-specific functions [7,8,[12], [13], [14], [15]]. The role of FPRs and their ligands in innate immunity, particularly neutrophil chemotaxis, is well established and has been demonstrated in many models of acute inflammation [7,8,16,17]. FPRs have been also implicated in the development of RA using acute models of the disease. For example, studies using mice deficient in FPR2 have demonstrated an inhibitory role of the receptor in K/B × N serum transfer arthritis [18]. Similarly, endogenous AnxA1, which exerts its effects mainly via FPR2, and in some cases FPR1 [[18], [19], [20], [21]], has an anti-inflammatory role in various models of acute inflammation [[21], [22], [23]] and in innate models of RA including K/B × N serum transfer arthritis and buy norethisterone arthritis [24,25]. The critical role of FPRs in inflammation has made them important potential therapeutic targets with the development of small molecules acting as specific ligands of FPRs to treat inflammatory conditions. One such molecule, compound 43 (Cpd43), a pyrazolone derivative, is a highly specific agonist of FPR2 and FPR1 [26,27]. It suppressed chemoattractant-induced neutrophil migration in vitro and in vivo, and attenuated joint injury in the acute K/B × N arthritis model [18,24,27]. The role of FPRs in adaptive immunity is less clear, but they can affect the initiation of T cell responses. For example, FPR1 and FPR2 can affect dendritic cell function, as well as T cell activation and differentiation [20,28,29]. Similarly, AnxA1 plays a role in the induction phase of T cell-driven models including experimental autoimmune encephalomyelitis (EAE) and lupus nephritis, as well as collagen-induced arthritis (CIA) and antigen-induced arthritis (AIA) [[30], [31], [32], [33]]. FPR2 is expressed by pre-activated CD4 T cells [9,10], however, very little is known about the role of FPRs and their ligands in effector T cell responses. Other than a few in vitro experiments showing that AnxA1 or AnxA1-derived peptides can inhibit antigen-specific proliferation and cytokine production of previously activated T cells [34,35], no other studies have reported findings about the role of FPRs or their ligands during the efferent phase of T cell immunity. Moreover, their effects on Tregs, which play a major immunosuppressive role in multiple immune-mediated diseases, are not well known. AnxA1 and FPR2, but not FPR1, are also expressed by FLS [24], the major local synovial cells which promote RA through their activation, expansion and resistance to apoptosis [36]. Although AnxA1, lipoxin A4 and Cpd43 have been shown to suppress FLS production of pro-inflammatory cytokines [24,37], the effect of FPR2 engagement by Cpd43 and AnxA1 on FLS proliferation or apoptosis has not been explored.
    Materials and methods
    Results
    Discussion CD4 T cells have a key role in AIA [2]. Here, decreased AIA severity due to Cpd43 treatment was associated with increased apoptosis of CD4 T cells. This finding is supported by reports showing that alternative FPR1/2 ligands such as AnxA1 promote apoptosis of other cells including neutrophils leading to resolution of inflammation [48]. Decreased CD4 survival, in turn, correlated with augmented proportion of foxp3+ Tregs, which are known to be inhibitory in AIA [1]. Moreover, Tregs from Cpd43-treated mice expressed higher levels of IL-2Rα (CD25), suggesting that these cells also have augmented immunosuppressive capacity. In addition, attenuated joint disease in mice receiving Cpd43 was associated with increased CD4 production of the anti-inflammatory Th2 cytokine, IL-4, which is suppressive in AIA [49]. Collectively, these results indicate that FPR activation by Cpd43 inhibits the progression of joint inflammation and damage in AIA by decreasing the survival of pathogenic effector CD4 T cells while augmenting Treg responses and skewing the immune response towards the protective Th2. Furthermore, our experiments with FPR inhibitors confirmed that Cpd43 suppresses AIA and arthritogenic T cell immunity via FPR2.