The N-formyl peptide receptors and the anaphylatoxin C5a receptors: An overview

Abstract

Leukocyte recruitment to sites of inflammation and infection is dependent on the presence of a gradient of locally produced chemotactic factors. This review is focused on current knowledge about the activation and regulation of chemoattractant receptors. Emphasis is placed on the members of the N-formyl peptide receptor family, namely FPR (N-formyl peptide receptor), FPRL1 (FPR like-1) and FPRL2 (FPR like-2), and the complement fragment C5a receptors (C5aR and C5L2). Upon chemoattractant binding, the receptors transduce an activation signal through a G protein-dependent pathway, leading to biochemical responses that contribute to physiological defense against bacterial infection and tissue damage. C5aR, and the members of the FPR family that were previously thought to be restricted to phagocytes proved to have a much broader spectrum of cell expression. In addition to N-formylated peptides, numerous unrelated ligands were recently found to interact with FPR and FPRL1. Novel agonists include both pathogen- and host-derived components, and synthetic peptides. Antagonistic molecules have been identified that exhibit limited receptor specificity. How distinct ligands can both induce different biological responses and produce different modes of receptor activation and unique sets of cellular responses are discussed. Cell responses to chemoattractants are tightly regulated at the level of the receptors. This review describes in detail the regulation of receptor signalling and the multi-step process of receptor inactivation. New concepts, such as receptor oligomerization and receptor clustering, are considered. Although FPR, FPRL1 and C5aR trigger similar biological functions and undergo a rapid chemoattractant-mediated phosphorylation, they appear to be differentially regulated and experience different intracellular fates.

Formyl Peptide Receptor-1 Activation Enhances Intestinal Epithelial Cell Restitution through Phosphatidylinositol 3-Kinase-Dependent Activation of Rac1 and Cdc42

“…Thus, the coordinate activities of these GTPases are required to induce the significant enhancement of wound closure induced by FPR stimulation. RhoA, RhoB, RhoC activity are also known to be induced by FPR stimulation; however, this was not observed in our system (13,14). Additionally, selective inhibition of RhoA, RhoB, RhoC using DC3B (C3 transferase) did not impair the fMLF-induced increase in SK-CO15 cell wound closure (data not shown).…”

“…In different cell types, including epithelial cells, PI3K regulates cell migration through a variety of downstream signaling molecules including Rho GTPases (12)(13)(14). Rho GTPase family members (Rac1, Cdc42, and RhoA) are central regulators of F-actin reorganization and thus play a crucial role in the migration of various cell types (15)(16)(17)(18).…”

Complement and its role in innate and adaptive immune responses

“…The functional responses of anaphylatoxins are mediated by their interactions with cognate 7-transmembrane G-protein-coupled receptors (C3aR for C3a, C5aR/C5L2 for C5a) of the rhodopsin family [55][56][57][58][59][60]. Binding of anaphylatoxins to extracellular, N-terminal regions of the anaphylatoxin receptors allows conformational changes to the intracellular, C-terminal regions of the receptors, resulting in coupling to G-proteins, predominantly pertussis toxin-sensitive G iα , to induce downstream signaling cascades [61][62][63][64][65].…”

“…Binding of anaphylatoxins to extracellular, N-terminal regions of the anaphylatoxin receptors allows conformational changes to the intracellular, C-terminal regions of the receptors, resulting in coupling to G-proteins, predominantly pertussis toxin-sensitive G iα , to induce downstream signaling cascades [61][62][63][64][65]. Activities of anaphylatoxins are confined by cell types that express their receptors, predominantly thought to be cells of myeloid origin, including granulocytes (basophils, eosinophils, and neutrophils), monocytes/macrophages, mast cells, and some dendritic cells, although there are numerous reports of receptor expression in a number of nonmyeloid cell types [54,59,60,[66][67][68][69][70][71][72][73]. Inactivation of anaphylatoxin molecules is an important determinant of the duration and extent of their potent functions and represents an alternative mechanism to control complement activation.…”

Complement Receptors in Inflammation

“…However, ectopically expressed C5aR, and C5aR on cells of the hematopoietic lineage, can also couple to PTX-insensitive G 16 (Amatruda et al, 1993, Monk andPartridge, 1993). C5a-C5aR interaction leads to activation of several components of signaling pathway, including PI3K-, PLC 2, and phospholipase D (PLD) (Rabiet et al, 2007). C5aR can activate the transcription factor, cyclic AMP (cAMP) response element-binding protein (CREB), by phosphorylation at the convergence of two pathways, PI3K/Akt and ERK (Perianayagam et al, 2006).…”