Lysophosphatidic Acid-Mediated GPR35 Signaling in CX3CR1+ Macrophages Regulates Intestinal Homeostasis

• DOI: 10.1016/j.celrep.2020.107979
• Publication Date: 2020-08-04T14:28:59Z
• Authors: Berna Kaya; Cristian Doñas; Philipp Wuggenig; Oscar E. Diaz; Rodrigo A. Morales; Hassan Melhem; Pedro P. Hernández; Tanay Kaymak; Srustidhar Das; Petr Hruz; Yannick Franc; Florian Geier; C. Korcan Ayata; Eduardo J. Villab...; Jan Hendrik Niess
• Keywords: CX3CR1; Proinflammatory cytokine

Single-nucleotide polymorphisms in the gene encoding G protein-coupled receptor 35 (GPR35) are associated with increased risk of inflammatory bowel disease. However, mechanisms by which GPR35 modulates intestinal immune homeostasis remain undefined. Here, integrating zebrafish and mouse experimental models, we demonstrate that Gpr35 expression is microbiota dependent enhanced upon inflammation. Moreover, murine GPR35+ colonic macrophages characterized production pro-inflammatory cytokines. We identify lysophosphatidic acid (LPA) as a potential endogenous ligand produced during inflammation, acting through to induce tumor necrosis factor (Tnf) macrophages. Mice lacking CX3CR1+ aggravate colitis when exposed dextran sodium sulfate, decreased transcript levels corticosterone-generating Cyp11b1 macrophage-derived Tnf. Administration TNF these mice restores corticosterone ameliorates DSS-induced colitis. Our findings indicate LPA signals maintain TNF-mediated homeostasis.