20 Years an Orphan: Is GPR84 a Plausible Medium-Chain Fatty Acid-Sensing Receptor?

Abstract

GPR84 is an inflammation-induced receptor highly expressed on immune cells, yet its endogenous ligand is still unknown. This makes any interpretation of its physiological activity in vivo difficult. However, experiments with potent synthetic agonists have highlighted what the receptor can do, namely, enhance proinflammatory signaling and macrophage effector functions such as phagocytosis. Developing drugs to block these effects has attracted interest from the scientific community with the aim of decreasing disease activity in inflammatory disorders or enhancing inflammation resolution. In this review, we critically reassess the widely held belief that the major role of GPR84 is that of being a medium-chain fatty acid (MCFA) receptor. While MCFAs have been shown to activate GPR84, it remains to be demonstrated that they are present in relevant tissues at appropriate concentrations. In contrast to four other ''full-time'' free fatty acid receptor subtypes, GPR84 is not expressed by enteroendocrine cells and has limited expression in the gastrointestinal tract. Across multiple tissues and cell types, the highest expression levels of GPR84 are observed hours after exposure to an inflammatory stimulus. These factors obscure the relationship between ligand and receptor in the human body and do not support the exclusive physiological pairing of MCFAs with GPR84. To maximize the chances of developing efficacious drugs for inflammatory diseases, we must advance our understanding of GPR84 and what it does in vivo.

Discovery and Characterization of Novel Antagonists of the Proinflammatory Orphan Receptor GPR84

“…TIP3P water molecules 36 were used to solvate the bilayer and counterions were added at a concentration of 0.15 M NaCl. The final systems comprised of ∼86 000 atoms with a box dimension of 90 × 90 × 114 Å 3 .…”

“…Although medium chain length fatty acids (MCFAs) have been known for a considerable period of time to be able to activate the G protein-coupled receptor (GPCR) GPR84, − this receptor remains classified as an “orphan”, i.e. that the true activator(s) of the receptor remain undefined or uncertain .…”

“…that the true activator(s) of the receptor remain undefined or uncertain . Expressed by a variety of immune cells, including monocytes, macrophages, and neutrophils in the periphery, and microglia in the brain ,, as well as tissues such as adipocytes and skeletal muscle, GPR84 has recently attracted considerable interest as a therapeutic target. In significant part, this reflects that GPR84 transcript and protein level is upregulated in many proinflammatory conditions and directly in response to proinflammatory stimuli. ,− This suggests that blocking the receptor might have value both in limiting the development of inflammatory conditions and during their resolution.…”

Modulation of the G-Protein-Coupled Receptor 84 (GPR84) by Agonists and Antagonists

“…These data indicate that GPR84 may be a target of therapeutic value, and all GPR84 ligands with activating or inhibitory effects may have potential clinical applications (Figure ). Recently, three excellent reviews have been published, which summarize the up-to-date research progress of GPR84, including its biological functions and ligand discovery, and reassess the belief of GPR84’s major role as an MCFA receptor. − In this Perspective, we focus on the recent advances of GPR84 ligands, their roles in the study of GPR84-mediated functions, and their potential applications in treating GPR84-related disease.…”

Metabolite G-Protein Coupled Receptors in Cardio-Metabolic Diseases

“…GPR84 : GPR84 binds MCFAs, and is expressed in immune cells from bone marrow, spleen, lung, lymph nodes, and adipose tissue [ 52 , 53 ]. GPR84 is predominantly a proinflammatory receptor and links fatty acid metabolism and immune responses; however, studies are limited [ 54 ].…”