Lysophosphatidic acid-mediated GPR35 signaling in CX3CR1+ macrophages regulates the intestinal cytokine milieu

Abstract

Single nucleotide polymorphisms in the gene encoding G protein-coupled receptor 35 (GPR35) are associated with increased risk of inflammatory bowel disease. However, the mechanism(s) by which GPR35 modulates the intestinal milieu remain undefined. Here we demonstrate in zebrafish and mice that expression of Gpr35 is microbiota-dependent and is enhanced upon inflammation. We identify a GPR35+ colonic macrophage population in mice that is characterized by increased production of pro-inflammatory cytokines, and determine that lysophosphatidic acid (LPA) acts as an endogenous GPR35 ligand to induce Tnf expression. Mice lacking Gpr35 in CX3CR1+ macrophages have aggravated colitis when exposed to dextran sodium sulfate, have decreased transcript levels of the corticosterone-generating gene Cyp11b1, and reduced levels of macrophage-derived TNF. Administration of TNF in these mice restores Cyp11b1 expression and intestinal corticosterone production, and ameliorates DSS-induced colitis. These findings suggest that LPA signals through GPR35 in CX3CR1+ macrophages to control the intestinal cytokine milieu. HighlightsO_LIInflammatory cues and the microbiota modulate Gpr35 expression across species C_LIO_LILPA modulates GPR35-dependent functions in zebrafish and mice macrophages C_LIO_LIGPR35 expressing macrophages have a protective role during intestinal inflammation C_LIO_LIGPR35 control intestinal inflammation by inducing TNF and corticosterone synthesis C_LI eTOC BlurbGPR35 have been associated with IBD, but how GPR35 may influence macrophage-mediated intestinal homeostasis remains unclear. Using zebrafish and mice genetic tools, Niess, Villablanca, and colleagues have identified that LPA triggers GPR35 activity, and loss of macrophage GPR35 signaling confers intrinsic dysfunctions with effects on cytokine production and intestinal homeostasis.