Succinate receptor mediates intestinal inflammation and fibrosis

• Published in: Mucosal immunology Vol. 12; no. 1; pp. 178 - 187
• Main Authors: Macias-Ceja, Dulce C., Ortiz-Masiá, Dolores, Salvador, Pedro, Gisbert-Ferrándiz, Laura, Hernández, Carlos, Hausmann, Martin, Rogler, Gerhard, Esplugues, Juan V., Hinojosa, Joaquín, Alós, Rafael, Navarro, Francisco, Cosin-Roger, Jesus, Calatayud, Sara, Barrachina, María D.
• Format: Journal Article
• Language: English
• Published: New York Elsevier Inc 01.01.2019; Nature Publishing Group US; Elsevier Limited
• Subjects: Adolescent; Adult; Allergology; Animals; Antibodies; Biomedical and Life Sciences; Biomedicine; CD86 antigen; Cell activation; Cells, Cultured; Colitis; Colitis - chemically induced; Colitis - immunology; Colon; Crohn Disease - immunology; Crohn's disease; Cytokines; Disease Models, Animal; Female; Fibroblasts; Fibrosis; Gastroenterology; Humans; Immune response; Immunology; Inflammation; Inflammation - immunology; Inflammatory bowel diseases; Intestinal Mucosa - metabolism; Intestinal Mucosa - pathology; Intestine; Macrophages; Macrophages - immunology; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Receptors, G-Protein-Coupled - genetics; Receptors, G-Protein-Coupled - metabolism; Rodents; Succinic Acid - metabolism; Tricarboxylic acid cycle; Young Adult
• ISSN: 1933-0219; 1935-3456; 1935-3456
• DOI: 10.1038/s41385-018-0087-3

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.