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Triggering the succinate receptor GPR91 on dendritic cells enhances immunity

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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References

  1. Banchereau, J. et al. Immunobiology of dendritic cells. Annu. Rev. Immunol. 18, 767–811 (2000).

    Article  CAS  Google Scholar 

  2. Parker, L.C., Prince, L.R. & Sabroe, I. Translational mini-review series on Toll-like receptors: networks regulated by Toll-like receptors mediate innate and adaptive immunity. Clin. Exp. Immunol. 147, 199–207 (2007).

    Article  CAS  Google Scholar 

  3. Sallusto, F. et al. Rapid and coordinated switch in chemokine receptor expression during dendritic cell maturation. Eur. J. Immunol. 28, 2760–2769 (1998).

    Article  CAS  Google Scholar 

  4. Marsland, B.J. et al. CCL19 and CCL21 induce a potent proinflammatory differentiation program in licensed dendritic cells. Immunity 22, 493–505 (2005).

    Article  CAS  Google Scholar 

  5. Matzinger, P. Tolerance, danger, and the extended family. Annu. Rev. Immunol. 12, 991–1045 (1994).

    Article  CAS  Google Scholar 

  6. Oppenheim, J.J. & Yang, D. Alarmins: chemotactic activators of immune responses. Curr. Opin. Immunol. 17, 359–365 (2005).

    Article  CAS  Google Scholar 

  7. He, W.H. et al. Citric acid cycle intermediates as ligands for orphan G-protein-coupled receptors. Nature 429, 188–193 (2004).

    Article  CAS  Google Scholar 

  8. Geissmann, F., Jung, S. & Littman, D.R. Blood monocytes consist of two principal subsets with distinct migratory properties. Immunity 19, 71–82 (2003).

    Article  CAS  Google Scholar 

  9. Larrick, J.W., Fischer, D.G., Anderson, S.J. & Koren, H.S. Characterization of a human macrophage-like cell-line stimulated in vitro - a model of macrophage functions. J. Immunol. 125, 6–12 (1980).

    CAS  PubMed  Google Scholar 

  10. Kono, H. & Rock, K.L. How dying cells alert the immune system to danger. Nat. Rev. Immunol. 8, 279–289 (2008).

    Article  CAS  Google Scholar 

  11. Xu, G. & Shi, Y. Apoptosis signaling pathways and lymphocyte homeostasis. Cell Res. 17, 759–771 (2007).

    Article  CAS  Google Scholar 

  12. Gallucci, S., Lolkema, M. & Matzinger, P. Natural adjuvants: endogenous activators of dendritic cells. Nat. Med. 5, 1249–1255 (1999).

    Article  CAS  Google Scholar 

  13. Shi, Y., Zheng, W. & Rock, K.L. Cell injury releases endogenous adjuvants that stimulate cytotoxic T cell responses. Proc. Natl. Acad. Sci. USA 97, 14590–14595 (2000).

    Article  CAS  Google Scholar 

  14. Shi, Y., Evans, J.E. & Rock, K.L. Molecular identification of a danger signal that alerts the immune system to dying cells. Nature 425, 516–521 (2003).

    Article  CAS  Google Scholar 

  15. Kool, M. et al. Alum adjuvant boosts adaptive immunity by inducing uric acid and activating inflammatory dendritic cells. J. Exp. Med. 205, 869–882 (2008).

    Article  CAS  Google Scholar 

  16. Shi, Y., Galusha, S.A. & Rock, K.L. Cutting edge: elimination of an endogenous adjuvant reduces the activation of CD8 T lymphocytes to transplanted cells and in an autoimmune diabetes model. J. Immunol. 176, 3905–3908 (2006).

    Article  CAS  Google Scholar 

  17. Kushnir, M.M., Komaromy-Hiller, G., Shushan, B., Urry, F.M. & Roberts, W.L. Analysis of dicarboxylic acids by tandem mass spectrometry. High-throughput quantitative measurement of methylmalonic acid in serum, plasma, and urine. Clin. Chem. 47, 1993–2002 (2001).

    CAS  PubMed  Google Scholar 

  18. Rotstein, O.D., Pruett, T.L., Fiegel, V.D., Nelson, R.D. & Simmons, R.L. Succinic acid, a metabolic by-product of bacteroides species, inhibits polymorphonuclear leukocyte function. Infect. Immun. 48, 402–408 (1985).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Correa, P.R. et al. Succinate is a paracrine signal for liver damage. J. Hepatol. 47, 262–269 (2007).

    Article  CAS  Google Scholar 

  20. Fiers, W., Beyaert, R., Declercq, W. & Vandenabeele, P. More than one way to die: apoptosis, necrosis and reactive oxygen damage. Oncogene 18, 7719–7730 (1999).

    Article  CAS  Google Scholar 

  21. Kissenpfennig, A. et al. Dynamics and function of Langerhans cells in vivo: dermal dendritic cells colonize lymph node areas distinct from slower migrating Langerhans cells. Immunity 22, 643–654 (2005).

    Article  CAS  Google Scholar 

  22. Müller-Decker, K., Fürstenberger, G. & Marks, F. Keratinocyte-derived pro-inflammatory key mediators and cell viability as in vitro parameters of irritancy: a possible alternative to the Draize skin irritation test. Toxicol. Appl. Pharmacol. 127, 99–108 (1994).

    Article  Google Scholar 

  23. Matzinger, P. The danger model: a renewed sense of self. Science 296, 301–305 (2002).

    Article  CAS  Google Scholar 

  24. Winau, F. et al. Ito cells are liver-resident antigen-presenting cells for activating T cell responses. Immunity 26, 117–129 (2007).

    Article  CAS  Google Scholar 

  25. Charbonnier, A.S. et al. Macrophage inflammatory protein 3 α is involved in the constitutive trafficking of epidermal Langerhans cells. J. Exp. Med. 190, 1755–1767 (1999).

    Article  CAS  Google Scholar 

  26. Lametschwandtner, G. et al. Sustained T-bet expression confers polarized human TH2 cells with TH1-like cytokine production and migratory capacities. J. Allergy Clin. Immunol. 113, 987–994 (2004).

    Article  CAS  Google Scholar 

  27. Pawlak, M. et al. Zeptosens' protein microarrays: a novel high performance microarray platform for low abundance protein analysis. Proteomics 2, 383–393 (2002).

    Article  CAS  Google Scholar 

  28. Wulfkuhle, J.D. et al. Signal pathway profiling of ovarian cancer from human tissue specimens using reverse-phase protein microarrays. Proteomics 3, 2085–2090 (2003).

    Article  CAS  Google Scholar 

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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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Authors

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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Competing interests

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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