Lysophosphatidic Acid-Mediated GPR35 Signaling in CX3CR1+ Macrophages Regulates Intestinal Homeostasis
- Kaya, B., Doñas, C., Wuggenig, P., Diaz, O.E., Morales, R.A., Melhem, H., Swiss IBD. Cohort Investigators, Hernández, P.P., Kaymak, T., Das, S., Hruz, P., Franc, Y., Geier, F., Ayata, C.K., Villablanca, E.J., Niess, J.H.
- Cell Reports 32: 107979 (Journal)
- Registered Authors
- Diaz, Oscar E., Morales, Rodrigo A.
- CX3CR1, Cyp11b1, GPR35, IBD, colitis, intestine, lysophosphatidic acid, macrophages, tumor necrosis factor, zebrafish
- MeSH Terms
- CX3C Chemokine Receptor 1/metabolism*
- Colitis/chemically induced
- Dextran Sulfate
- Gastrointestinal Microbiome
- Gene Deletion
- Inflammatory Bowel Diseases/pathology
- Mice, Inbred C57BL
- Phosphoric Diester Hydrolases/metabolism
- Receptors, G-Protein-Coupled/metabolism*
- Signal Transduction*
- Tumor Necrosis Factor-alpha/antagonists & inhibitors
- Tumor Necrosis Factor-alpha/metabolism
- Zebrafish Proteins/metabolism*
- 32755573 Full text @ Cell Rep.
Kaya, B., Doñas, C., Wuggenig, P., Diaz, O.E., Morales, R.A., Melhem, H., Swiss IBD. Cohort Investigators, Hernández, P.P., Kaymak, T., Das, S., Hruz, P., Franc, Y., Geier, F., Ayata, C.K., Villablanca, E.J., Niess, J.H. (2020) Lysophosphatidic Acid-Mediated GPR35 Signaling in CX3CR1+ Macrophages Regulates Intestinal Homeostasis. Cell Reports. 32:107979.
Single-nucleotide polymorphisms in the gene encoding G protein-coupled receptor 35 (GPR35) are associated with increased risk of inflammatory bowel disease. However, the mechanisms by which GPR35 modulates intestinal immune homeostasis remain undefined. Here, integrating zebrafish and mouse experimental models, we demonstrate that intestinal Gpr35 expression is microbiota dependent and enhanced upon inflammation. Moreover, murine GPR35+ colonic macrophages are characterized by enhanced production of pro-inflammatory cytokines. We identify lysophosphatidic acid (LPA) as a potential endogenous ligand produced during intestinal inflammation, acting through GPR35 to induce tumor necrosis factor (Tnf) expression in macrophages. Mice lacking Gpr35 in CX3CR1+ macrophages aggravate colitis when exposed to dextran sodium sulfate, which is associated with decreased transcript levels of the corticosterone-generating gene Cyp11b1 and macrophage-derived Tnf. Administration of TNF in these mice restores Cyp11b1 expression and intestinal corticosterone production and ameliorates DSS-induced colitis. Our findings indicate that LPA signals through GPR35 in CX3CR1+ macrophages to maintain TNF-mediated intestinal homeostasis.
Genes / Markers
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Engineered Foreign Genes