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  • The first FPR ligand described is the fMLF peptide


    The first FPR1 ligand described is the fMLF peptide, which binds with high affinity (in the nM range) to and activates FPR1. Formylated peptides derived from Listeria monocytogenes also selectively activate FPR1 [10] (Table 1). Formylation of peptides also occurs in mitochondria. Thus, the release of formylated peptides secondary to cell death might allow attraction of phagocytic leukocytes through FPRs [2]. FPR2, aka “lipoxin A4 (LXA4) receptor (ALX/FPR2)”, is considered a low-affinity receptor for formylated peptides given its activation upon exposure to high fMLF concentrations (in the μM range) in vitro [11] (Table 2). FPR3 does not bind or respond to fMLF, and shares some non-formylated chemotactic peptide ligands with FPR2 [3] (Table 3). Ligand diversity is a feature of the FPR family (Tables 1-3) (Fig. 1). In the last 10 years, several natural and synthetic small-molecular-weight, even non-formylated, ligands for FPRs have been identified through insulin receptor library screening. Amongst agonists, several microbe-derived formylated or non-formylated peptides have been identified that can bind FPRs. In addition to “exogenous”, a large number of “endogenous” peptides of various molecular nature, functioning as DAMPs, have been identified as agonists at FPRs [3] (Table 1, Table 2, Table 3) (Fig. 1). Some FPR agonists can activate FPR anti-inflammatory signalling properties: annexin A1 (AnxA1) and its N-terminal peptide Ac2–26, and the two nonpeptidic ligands lipoxin A4 (LXA4) and resolvin D1 (RvD1) [12] (Table 2). Among antagonists, cyclosporin H (CsH), an optical isomer of the immunosuppressant cyclosporin A, is a cyclic undecapeptide produced by fungi that displays selective antagonistic activity at human FPR1 [13], [14] (Table 1).
    FPRs and angiogenesis Angiogenesis, the formation of new blood vessels, is involved in both physiologic and pathologic processes. Indeed, physiological tissue function depends on an adequate supply of nutrients and oxygen through the blood vessels. Wound healing, after tissue damage, requires a complex network of cellular and molecular events [36] including cell migration, proliferation, and angiogenesis [37]. The angiogenic response is also involved in such pathologic conditions as chronic and acute inflammatory disorders (i.e. rheumatoid arthritis, Crohn's disease, and infections) [36], metabolic diseases (i.e. diabetes) [38], and cancer [39]. It is well established that FPRs can modulate the expression and secretion of angiogenic factors from different cell types in vitro. However, the knowledge of FPR functions in this context is limited.
    Other roles of FPRs in cancer FPR functions have been studied in depth in other cancer histotypes besides the above mentioned. Liu et al. demonstrated that FPR activation suppresses melanoma development. In their experimental model, FPR activation by WKYMVm, an FPR panagonist [15], inhibited B16 melanoma cell growth in xenotransplants by reducing infiltration of protumorigenic myeloid derived suppressor cells (MDSCs) and increasing anti-tumour NK cells. The tumour suppressor effect of WKYMVm was dependent on intratumoral NK migration, since NK-depletion abrogated the FPR-mediated tumour suppressor effects. Markers of M1 anti-tumorigenic macrophages were significantly higher and M2 pro-tumorigenic macrophages significantly lower in WKYMVm-treated mice than in untreated mice. Thus, these results open the possibility that FPR stimulation could be a new therapeutic target for melanoma due to its immunomodulatory effects on tumour infiltrating cells [74]. Recently, Chen and collaborators studied the role of murine FPRs in colon mucosa functions [35]. They showed that functional mFPR2 was expressed on the apical and lateral membrane of mouse colonic epithelial cells. mFPR2 played a more prominent role in maintaining the normal growth of colonic epithelial cells than mFPR1, since mFPR2–/– mouse colon contained significantly shortened crypts and a diminished number of proliferating epithelial cells compared to controls. Interestingly, this study also showed that mFPR2 is involved in colonic mucosal repair, since upon DSS intake prolonged chronic inflammation in the colon occurred in mFPR2–/– mice. Importantly, mFPR2-deficiency markedly increased the tumour burden associated with chronic insulin receptor inflammation. In fact, mFPR2–/– mice were more susceptible to colon tumorigenesis induced by the carcinogen azoxymethane followed by DSS injury. The importance of mFPR2 in epithelial cells, rather than immune cells, was confirmed by results obtained in mice with specific ablation of mFPR2 in colonic epithelial cells. Thus, mFPR2 is crucial for colonic mucosal homeostasis, inflammation and cancer [35].