Formyl peptide receptors in the mucosal immune system

Abstract

Formyl peptide receptors (FPRs) belong to the G protein-coupled receptor (GPCR) family and are well known as chemotactic receptors and pattern recognition receptors (PRRs) that recognize bacterial and mitochondria-derived formylated peptides. FPRs are also known to detect a wide range of ligands, including host-derived peptides and lipids. FPRs are highly expressed not only in phagocytes such as neutrophils, monocytes, and macrophages but also in nonhematopoietic cells such as epithelial cells and endothelial cells. Mucosal surfaces, including the gastrointestinal tract, the respiratory tract, the oral cavity, the eye, and the reproductive tract, separate the external environment from the host system. In mucosal surfaces, the interaction between the microbiota and host cells needs to be strictly regulated to maintain homeostasis. By sharing the same FPRs, immune cells and epithelial cells may coordinate pathophysiological responses to various stimuli, including microbial molecules derived from the normal flora. Accumulating evidence shows that FPRs play important roles in maintaining mucosal homeostasis. In this review, we summarize the roles of FPRs at mucosal surfaces.

Fig. 1. Functional roles of FPRs in the regulation of immune responses in the GI tract.

a Neutrophils migrate into the inflamed GI tract toward various chemoattractants. In the case of Toxoplasma gondii and bacterial infection, neutrophils migrate to the gut lumen in an FPR1-dependent manner to regulate bacterial containment and to separate luminal contents from the epithelium. Neutrophils activated by FPR1 remove microenvironmental oxygen by NOX2-mediated ROS generation, resulting in local enrichment of an anaerobic bacterial consortium. In particular, Akkermansia muciniphila facilitates epithelial wound healing through an epithelial NOX1-dependent mechanism. Monocytes, which facilitate epithelial remodeling during wound closure, migrate into the inflamed site via the CCL20-CCR6 axis. FPR2 expression is related to the expression of CCR6 in monocytes. b M cells and DCs in Peyer’s patches recognize LL-37 via FPR2, promoting DC activation with increased phagocytosis, expression of CD40, and production of IL-6 and IL-12. Follicular DCs express CXCL13 and B cell-activating factor, supporting germinal center B cell activation in Peyer’s patches via FPR2 signaling.

Fig. 2. Functional roles of FPRs in the regulation of respiratory diseases.

a Smoking induces lung damage and structural changes, eliciting augmented bacterial colonization in the lower respiratory tract, with increased production of fMLP. b In COPD, inflammatory FPR2 ligands are produced at higher levels than anti-inflammatory FPR ligands. c Klebsiella pneumoniae infection stimulates BALF cells to produce LXA4, which induces an anti-inflammatory response leading to bacterial dissemination in the early phase of infection and is required for resolution and recovery in the late phase of infection. However, FPR2 is required for maintaining epithelial integrity against Streptococcus pneumoniae infection. d AnxA1 is incorporated into influenza A virus particles, stimulating FPR2-mediated signaling to block defense activity against virus infection.