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.

Modified Signaling of Membrane Formyl Peptide Receptors in NADPH-Oxidase Regulation in Obesity-Resistant Mice

“…Operating through membrane receptors on the cell surface belonging to the FPR family, N-formyl peptides are a driver of migration and activators of different granulocyte functions among which ROS generation is one of the most important. Granulocytes regulated through various receptors are inducers of inflammation and participants of its completion or transition to the chronic stage in pathologies [ 8 , 40 , 41 , 42 , 43 ]. Based on the abovementioned, we assumed that in HFD-consuming ORM the ability of granulocytes to produce ROS in response to activation of FPRs is modified under basic conditions and with the development of acute inflammation.…”

“…The WKYMVM signal allowed us to distinguish acute inflammation in controls. This situation can be due to features of binding of peptides with FPRs, receptor expression, state (e.g., desensitization in ORM), or signaling [ 8 , 12 , 48 , 49 , 50 , 51 ]. Next, we analyzed FPR signaling to NADPH-oxidase with the participation of PLC, and PKC, as the main signaling components of these receptors, as well as MAPKs, which fine-tune the activity of the oxidase and participate in pathological processes.…”

“…Obese inflammatory conditions in different tissues are triggered and maintained by such epigenetics factors as dietary components (fatty acids including), hypoxia, danger/pathogen-associated molecular patterns (DAMP/PAMPs–LPS, C-type lectins, N-formyl peptides, structure fragments of pathogens, and DNA), and intestinal microbiota (alterations of which can lead to metabolic endotoxemia owing to raised plasma levels of LPS) [ 6 , 7 ]. The inflammatory state evinces increased serum concentrations of C-reactive protein, and is accompanied by an excessive level of proinflammatory cytokines (TNF-α, IL-1β, IL-6, IL-8) and decreased production of regulators with anti-inflammatory properties (IL-10, IL-4, TGF-β, prostaglandin E2, factors controlling Toll-like receptors, and NF-κB signaling) [ 2 , 8 ]. Epigenetic regulation of Toll-like receptors (TLRs–TLR2 and TLR4) via changes in the gut microbiota correlated significantly with body mass index [ 1 ].…”

“…Fpr1 and Fpr2, receptors with high- and low-affinity to fMLF, accordingly, are predominantly expressed in mouse neutrophils. Their roles in inflammation are different: FPR1 is considered to be the primary receptor for detection of N-formyl peptides, whereas FPR2 (69% homology to FPR1) can bind to a variety of ligands (formyl peptides, annexin A1, serum amyloid A, lipoxin A4, and others) [ 8 , 9 , 11 ]. FPR2 mediates both inflammatory and anti-inflammatory functions, suggesting ligand-dependent biased signaling; it is considered as a therapeutic target in inflammation, in particular for bowel disease [ 8 ].…”

“…Their roles in inflammation are different: FPR1 is considered to be the primary receptor for detection of N-formyl peptides, whereas FPR2 (69% homology to FPR1) can bind to a variety of ligands (formyl peptides, annexin A1, serum amyloid A, lipoxin A4, and others) [ 8 , 9 , 11 ]. FPR2 mediates both inflammatory and anti-inflammatory functions, suggesting ligand-dependent biased signaling; it is considered as a therapeutic target in inflammation, in particular for bowel disease [ 8 ]. Both receptors have been attributed a role in obesity: the FPR1 gene was downregulated in obese humans, and CYBB gene-coding NADPH-oxidase membrane subunit gp91phox was also downregulated in obese humans [ 12 ]; genetic or pharmacological inhibition of Fpr1 increased insulin levels and improved glucose tolerance, dependent upon glucagon-like peptide 1 [ 9 ]; the lack of ALX/FPR2 led to the development of spontaneous obesity, reduced life span, amplified leukocyte dysfunction, and facilitated profound interorgan non-resolving inflammation [ 13 ].…”