Formyl peptide receptor 2 as a potential therapeutic target for inflammatory bowel disease

Abstract

Inflammatory bowel disease (IBD) is a global health burden whose existing treatment is largely dependent on anti-inflammatory agents. Despite showing some therapeutic actions, their clinical efficacy and adverse events are unacceptable. Resolution as an active and orchestrated phase of inflammation involves improper inflammatory response with three key triggers, specialized pro-resolving mediators (SPMs), neutrophils and phagocyte efferocytosis. The formyl peptide receptor 2 (FPR2/ALX) is a human G protein-coupled receptor capable of binding SPMs and participates in the resolution process. This receptor has been implicated in several inflammatory diseases and its association with mouse model of IBD was established in some resolution-related studies. Here, we give an overview of three reported FPR2/ALX agonists highlighting their respective roles in pro-resolving strategies.

Keywords: FPR2/ALX; IBD; SPM; inflammation; pro-resolving; resolution.

Fig. 1. Typical studies regarding IBD treatment using pro-resolving strategies.

BLT1 B-type leukotriene 1, CAC colitis-associated cancer, CD Crohn’s disease, Chemerin1 (ChemR23) chemokine receptor-like 1, DSS dextran sulfate sodium, EP4 E-type prostanoid receptor 4, FPR2/ALX formyl peptide receptor 2, GPCR G protein-coupled receptor, IBD inflammatory bowel disease, IECs intestinal epithelial cells, LGR6 leucine-rich repeat-containing G-protein coupled receptor 6, LXA4 lipoxin A4, mAb monoclonal antibody, MaR1 maresin 1, PD1n-3 n-3 protectin D1, PGE2 prostaglandin E2, RvD1 D series resolvin 1, TNBS 2,4,6-trinitrobenzene sulfonic acid, UC ulcerative colitis, SPMs specialized pro-resolving mediators. This figure was generated by an open-type platform FigDraw (http://www.figdraw.com/).

Fig. 2. Potential mechanisms of FPR2/ALX mediated responses induced by various ligands.

Like other chemoattractant receptors, FPR2/ALX couples to the G_i class of heterotrimeric G proteins. Bifurcation of FPR2/ALX signaling exists. a Some ligands like amyloid β_1-42 (Aβ_1-42) and serum amyloid A (SAA) can activate FPR1 to trigger pro-inflammatory signals directly, or they activate FPR2/ALX by coupling to Gα_i resulting in Ca²⁺ mobilization and ERK phosphorylation, thereby showing biased pro-inflammation. b Most FPR2/ALX agonists (LXA4, AnxA1, Ac2-26, ATL, RvD1 and Quin-C1) induce biased pro-resolving signals via β-arrestin 2 recruitment, cAMP production and p38 MAPK phosphorylation. c Heterologous desensitization of FPR2/ALX is probably mediated by β-arrestins. FPR2/ALX is phosphorylated by G protein-coupled receptor kinases (GRKs) to recruit β-arrestins, which then inhibit protein kinase A/C (PKA/PKC) signaling pathways. d FPR2/ALX internalization is essential to LXA4- and AnxA1-stimulated pro-resolution as the internalized receptor inhibits NF-κB activity. Some desensitized FPR2/ALX receptors are also internalized into cells. This figure was generated by an open-type platform FigDraw (http://www.figdraw.com/).

Fig. 3. FPR2/ALX in the resolution of inflammation.

Taking the gastrointestinal tract as a model, when injury or infection occurs, neutrophils migrate to the inflamed site attracted by chemokines. DAMPs and PAMPs invade via IECs to the damaged tissues and the production of pro-inflammatory cytokines is up-regulated to clear pathogens after activating T helper (Th) cells, resulting in inflammatory response. In the resolution phase, an increase in SPMs is accompanied by a decrease in pro-inflammatory cytokines. After recognizing LL-37 (an anti-microbial peptide) and SPMs via FPR2/ALX, DCs are activated with elevated phagocytosis and CD40 expression to clear PAMP and DAPM signals. Upon completing their mission of resisting pathogen invasion, neutrophils enter into the apoptosis process associated with SPMs and FPR2/ALX. SPMs reprogram macrophages towards M2 pro-resolving phenotypes, and apoptotic neutrophils are phagocytosed by M2 macrophages thereafter. FPR2/ALX expression is related to that of CCR6 in monocytes thereby facilitating the latter to the inflamed site and the epithelial remodeling in the wound. CCR chemokine receptor; DAMP damage-associated molecular pattern; DC dendritic cell; FPR2/ALX formyl peptide receptor 2; IEC intestinal epithelial cell; PAMP pathogen-associated molecular pattern; SPM specialized pro-resolving mediator. This figure was generated by an open-type platform FigDraw (http://www.figdraw.com/).