Lysophosphatidic acid-mediated GPR35 signaling in CX3CR1+macrophages regulates the intestinal cytokine milieu
| Autor: | Kaya, Berna, Cuadra, Cristian Doñas, Wuggenig, Philipp, Diaz, Oscar E., Morales, Rodrigo A., Melhem, Hassan, Hernández, Pedro P., Kaymak, Tanay, Das, Srustidhar, Hruz, Petr, Ayata, C. Korcan, Villablanca, Eduardo J., Niess, Jan Hendrik |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
biology Gut flora biology.organism_classification medicine.disease 03 medical and health sciences chemistry.chemical_compound 030104 developmental biology 0302 clinical medicine chemistry Downregulation and upregulation Lysophosphatidic acid Immunology medicine Tumor necrosis factor alpha Colitis Receptor GPR35 030215 immunology G protein-coupled receptor |
| Popis: | SummarySingle 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 ofGpr35is 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 induceTnfexpression. Mice lackingGpr35in CX3CR1+macrophages have aggravated colitis when exposed to dextran sodium sulfate, have decreased transcript levels of the corticosterone-generating geneCyp11b1, and reduced levels of macrophage-derived TNF. Administration of TNF in these mice restoresCyp11b1expression 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.HighlightsInflammatory cues and the microbiota modulateGpr35expression across speciesLPA modulates GPR35-dependent functions in zebrafish and mice macrophagesGPR35 expressing macrophages have a protective role during intestinal inflammationGPR35 control intestinal inflammation by inducing TNF and corticosterone synthesiseTOC 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. |
| Databáze: | OpenAIRE |
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