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Triggering the succinate receptor GPR91 on dendritic cells enhances immunity

Nature Immunology volume 9, pages 1261–1269 (2008)Cite this article

Abstract

Succinate acts as an extracellular mediator signaling through the G protein–coupled receptor GPR91. Here we show that dendritic cells had high expression of GPR91. In these cells, succinate triggered intracellular calcium mobilization, induced migratory responses and acted in synergy with Toll-like receptor ligands for the production of proinflammatory cytokines. Succinate also enhanced antigen-specific activation of human and mouse helper T cells. GPR91-deficient mice had less migration of Langerhans cells to draining lymph nodes and impaired tetanus toxoid–specific recall T cell responses. Furthermore, GPR91-deficient allografts elicited weaker transplant rejection than did the corresponding grafts from wild-type mice. Our results suggest that the succinate receptor GPR91 is involved in sensing immunological danger, which establishes a link between immunity and a metabolite of cellular respiration.

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Figure 1: Human iMoDCs have high expression of GPR91 transcripts and GPR91 expression is induced specifically during the differentiation from monocyte to iMoDC.
Figure 2: Succinate induces the mobilization of intracellular calcium in iMoDCs but not in their precursor monocytes.
Figure 3: Succinate mediates the chemotaxis of human iMoDCs and stimulates the production of inflammatory cytokines.
Figure 4: Triggering GPR91 on human iMoDCs with succinate enhances SEA- or tetanus toxoid–induced production of cytokines by human CD4+ T cells in a dose-dependent way.
Figure 5: GPR91 mediates the immunomodulatory effects of succinate.
Figure 6: Sucnr1−/− mice have impaired immune responses and DC migration.
Figure 7: Sucnr1−/− skin grafts elicit weaker allograft rejection responses in vivo than do the corresponding wild-type grafts.

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Acknowledgements

We thank M. Hahn, M. Hernusz and W. Höllriegl for animal husbandry, and S. Huber for assistance with genotyping Sucnr1−/− mice.

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Author notes

  1. Tina Rubic and Günther Lametschwandtner: These authors contributed equally to this work.

Authors and Affiliations

  1. Novartis Institutes for Biomedical Research, Vienna, A-1235, Austria

    Tina Rubic, Günther Lametschwandtner, Sandra Jost, Sonja Hinteregger, Julia Kund, Nicole Carballido-Perrig, Christoph Schwärzler, Tobias Junt, Josef G Meingassner, Gudrun Werner, Antal Rot & José M Carballido

  2. Novartis Institutes for Biomedical Research, Basel, CH-4002, Switzerland

    Tina Rubic, Nicole Carballido-Perrig, Christoph Schwärzler, Tobias Junt, Hans Voshol & José M Carballido

  3. Novartis Institutes for Biomedical Research, Cambridge, 02139, Massachusetts, USA

    Xiaohong Mao

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Contributions

T.R. and G.L. designed and did experiments, analyzed data and contributed to the writing of the manuscript; S.J., S.H., J.K., N.C.-P., H.V., J.G.M. and A.R. designed and did experiments; C.S., T.J., X.M. and G.W. provided critical material and helped analyze data; and J.M.C. initiated and directed the research, designed experiments, analyzed data and contributed to the writing of the manuscript.

Corresponding author

Correspondence to José M Carballido.

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All authors are employees of the Novartis Institutes for Biomedical Research and are engaged in drug development.

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Rubic, T., Lametschwandtner, G., Jost, S. et al. Triggering the succinate receptor GPR91 on dendritic cells enhances immunity. Nat Immunol 9, 1261–1269 (2008). https://doi.org/10.1038/ni.1657

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