Function and regulation of GPR84 in human neutrophils

Abstract

Human neutrophils are components of the innate immune system and are the most abundant white blood cells in the circulation. They are professional phagocytes and express several G protein‐coupled receptors (GPCRs), which are essential for proper neutrophil functions. So far, the two formyl peptide receptors, FPR1 and FPR2, have been the most extensively studied group of neutrophil GPCRs, but recently, a new group, the free fatty acid (FFA) receptors, has attracted growing attention. Neutrophils express two FFA receptors, GPR84 and FFA2, which sense medium‐ and short‐chain fatty acids respectively, and display similar activation profiles. The exact pathophysiological role of GPR84 is not yet fully understood, but it is generally regarded as a pro‐inflammatory receptor that mediates neutrophil activation. In this review, we summarize current knowledge of how GPR84 affects human neutrophil functions and discuss the regulatory mechanisms that control these responses, focusing on the similarities and differences in comparison to the two FPRs and FFA2.

Editorial for GPR84 pharmacology

“…Finally, to return focus to the roles of GPR84 in immune cell function, Huamei Forsman (University of Gothenburg) considered the roles of GPR84 using mostly human neutrophils as the experimental system (Forsman et al, 2024). Most notably, functions of GPR84 in relation to neutrophil NADPH oxidase activity and neutrophil priming were discussed, both when GPR84 was activated in isolation and when GPR84 was co-activated alongside either the short chain fatty acid receptor FFA2 or the FPR1 and FPR2 formyl peptide receptors.…”

Sensing of luminal contents and downstream modulation of GI function

“…48 The association between nutrients and neutrophils has been widely studied via GPCRs, specifically for FPR1, FRP2, and, recently, FFA2 and GPR84. 72 Both receptors FFA2 and GPR84 are involved in neutrophil degranulation, chemotactic migration, and production of NADPH oxidase-derived reactive oxygen species (ROS) in human and mice studies. 73 Likewise, GPR84 is also expressed on primary human monocytes, monocytes derived from macrophages, and macrophages.…”

“…73 Likewise, GPR84 is also expressed on primary human monocytes, monocytes derived from macrophages, and macrophages. 72 In inflammatory bowel disease (IBD), where there is significant immune activity, nutrient availability influences inflammatory pathways. In Crohn's disease, patients with enteral dietary fiber nutrition had increased FFA2 expression in polymorphs, which increased infiltration 74 , while surgical resection tissue had increased expression compared to controls.…”

“…Both receptors FFA2 and GPR84 are involved in neutrophil degranulation, chemotactic migration, and production of NADPH oxidase‐derived reactive oxygen species (ROS) in human and mice studies 73 . Likewise, GPR84 is also expressed on primary human monocytes, monocytes derived from macrophages, and macrophages 72 …”

PET Imaging of Innate Immune Activation Using 11C Radiotracers Targeting GPR84

“…GPR84, a seven-transmembrane domain orphan G-protein coupled receptor, is a new promising biomarker of innate immune activation. , The predominant expression of GPR84 on microglia in the CNS and peripheral myeloid cells (macrophages, monocytes, and neutrophils) make it an excellent candidate biomarker of innate immune responses. , Importantly, CNS injury and inflammatory stimuli are known to induce significant upregulation of GPR84 expression on pro-inflammatory microglia. For example, mice suffering from endotoxemia exhibit elevated GPR84 on microglia and, to a lesser extent, subpopulations of peripheral macrophages and monocytes .…”