GPR84 signaling promotes intestinal mucosal inflammation via enhancing NLRP3 inflammasome activation in macrophages

The putative medium-chain free fatty acid receptor, GPR84, is a G protein-coupled receptor predominantly found in myeloid cells such as neutrophils, monocytes, macrophages, and microglia in the brain. These cells are key components of the innate immune system. Notably, the expression of GPR84 in leukocytes is significantly elevated during acute inflammatory responses triggered by factors like lipopolysaccharide (LPS) and TNFα, suggesting a potential role in the progression of inflammatory and fibrotic diseases. Our findings indicate that GPR84 is substantially upregulated in the inflamed colon tissues of patients with active ulcerative colitis (UC) and mice with colitis induced by dextran sulfate sodium (DSS). There is a marked increase in GPR84-positive macrophages infiltrating the colonic mucosa of both UC patients and DSS-treated mice. Consistent with these observations, mice lacking the GPR84 gene (GPR84-/-) exhibit resistance to DSS-induced colitis. Activation of GPR84 enhances the pro-inflammatory properties of colonic macrophages by promoting NLRP3 inflammasome activation, whereas the absence of GPR84 inhibits the polarization and pro-inflammatory characteristics of M1 macrophages. Our novel GPR84 antagonist, CLH536, has been shown to suppress colitis by reducing the polarization and activity of pro-inflammatory macrophages. These findings highlight a distinct role of GPR84 in innate immune cells and intestinal inflammation, suggesting that GPR84 could be a promising therapeutic target GPR84 antagonist 8 for treating ulcerative colitis.