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Mucosal Immunol. 2019 Jan;12(1):178-187. doi: 10.1038/s41385-018-0087-3. Epub 2018 Oct 2.

Succinate receptor mediates intestinal inflammation and fibrosis.

Author information

1
Hospital Dr Peset, FISABIO, Valencia, Spain.
2
Departamento de Medicina, Facultad de Medicina, Universidad de Valencia, Valencia, Spain.
3
Departamento de Farmacología and CIBER, Facultad de Medicina, Universidad de Valencia, Valencia, Spain.
4
Department of Gastroenterology and Hepatology, University Hospital of Zurich, University of Zurich, Zurich, Switzerland.
5
Hospital de Manises, Valencia, Spain.
6
Hospital De Sagunto, Valencia, Spain.
7
Hospital Dr Peset, FISABIO, Valencia, Spain. jesus.cosin@uv.es.

Abstract

Succinate, an intermediate of the tricarboxylic acid cycle, is accumulated in inflamed areas and its signaling through succinate receptor (SUCNR1) regulates immune function. We analyze SUCNR1 expression in the intestine of Crohn's disease patients and its role in murine intestinal inflammation and fibrosis. We show that both serum and intestinal succinate levels and SUCNR1 expression in intestinal surgical resections were higher in CD patients than in controls. SUCNR1 co-localized with CD86, CD206, and α-SMA+ cells in human intestine and we found a positive and significant correlation between SUCNR1 and α-SMA expression. In human isolated fibroblasts from CD patients SUCNR1 expression was higher than in those from controls and treatment with succinate increased SUCNR1 expression, fibrotic markers and inflammatory cytokines through SUCNR1. This receptor modulated the expression of pro-inflammatory cytokines in resting murine macrophages, macrophage polarization and fibroblast activation and Sucnr1-/- mice were protected against both acute TNBS-colitis and intestinal fibrosis induced by the heterotopic transplant of colonic tissue. We demonstrate increased succinate levels in serum and SUCNR1 expression in intestinal tissue of CD patients and show a role for SUCNR1 in murine intestinal inflammation and fibrosis.

PMID:
30279517
DOI:
10.1038/s41385-018-0087-3

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