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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.

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Funding

This work was supported by the Ministerio de Economia, Industria y Competitividad and the European Regional Development fund of the European Union (ERDF) (SAF2016-80072P), CIBERehd (CB06/04/0071), and Generalitat Valenciana [PROMETEOII/2014/035, UGP-14-164, GV/2018/041].

Author's contributions

M.D.B., S.C., D.C.M.-C., J.C.-R., C.H., conceived the experiments and analyzed the data. M.D.B., S.C. wrote the manuscript. D.C.M.-C., J.C.-R., P.S., D.O.-M., L.G.-F., conducted the experiments. J.H., R.A., and F.L., provided human CD tissue samples and provided intellectual input. M.H., G.R., and J.V.E. provided intellectual input. All authors reviewed the manuscript.

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Author notes

  1. These authors contributed equally: Dulce C. Macias-Ceja, Dolores Ortiz-Masiá, Sara Calatayud, María D. Barrachina.

Affiliations

  1. Hospital Dr Peset, FISABIO, Valencia, Spain

    • Dulce C. Macias-Ceja
    • , Carlos Hernández
    • , Juan V. Esplugues
    •  & Jesus Cosin-Roger
  2. Departamento de Medicina, Facultad de Medicina, Universidad de Valencia, Valencia, Spain

    • Dolores Ortiz-Masiá
  3. Departamento de Farmacología and CIBER, Facultad de Medicina, Universidad de Valencia, Valencia, Spain

    • Pedro Salvador
    • , Laura Gisbert-Ferrándiz
    • , Juan V. Esplugues
    • , Sara Calatayud
    •  & María D. Barrachina
  4. Department of Gastroenterology and Hepatology, University Hospital of Zurich, University of Zurich, Zurich, Switzerland

    • Martin Hausmann
    •  & Gerhard Rogler
  5. Hospital de Manises, Valencia, Spain

    • Joaquín Hinojosa
    •  & Francisco Navarro
  6. Hospital De Sagunto, Valencia, Spain

    • Rafael Alós

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Competing interests

The authors declare no competing interests.

Corresponding author

Correspondence to Jesus Cosin-Roger.

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DOI

https://doi.org/10.1038/s41385-018-0087-3