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Metabotropic glutamate receptor-4 modulates adaptive immunity and restrains neuroinflammation

Nature Medicine volume 16, pages 897–902 (2010)Cite this article

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Abstract

High amounts of glutamate are found in the brains of people with multiple sclerosis, an inflammatory disease marked by progressive demyelination. Glutamate might affect neuroinflammation via effects on immune cells. Knockout mice lacking metabotropic glutamate receptor-4 (mGluR4) were markedly vulnerable to experimental autoimmune encephalomyelitis (EAE, a mouse model of multiple sclerosis) and developed responses dominated by interleukin-17–producing T helper (TH17) cells. In dendritic cells (DCs) from those mice, defective mGluR4 signaling—which would normally decrease intracellular cAMP formation—biased TH cell commitment to the TH17 phenotype. In wild-type mice, mGluR4 was constitutively expressed in all peripheral DCs, and this expression increased after cell activation. Treatment of wild-type mice with a selective mGluR4 enhancer increased EAE resistance via regulatory T (Treg) cells. The high amounts of glutamate in neuroinflammation might reflect a counterregulatory mechanism that is protective in nature and might be harnessed therapeutically for restricting immunopathology in multiple sclerosis.

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Figure 1: mGluR4-deficient mice are highly susceptible to EAE.
Figure 2: mGluR4 deficiency alters TH cell differentiation and cytokine production.
Figure 3: CD4+ T cells and DCs express the highest levels of mGluR4.
Figure 4: The absence of mGluR4 in DCs favors emergence of TH17 cells.
Figure 5: mGluR4-dependent signaling controls cAMP formation and cytokine production.
Figure 6: PHCCC attenuates EAE.

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References

  1. Woiciechowsky, C. et al. Sympathetic activation triggers systemic interleukin-10 release in immunodepression induced by brain injury. Nat. Med. 4, 808–813 (1998).

    Article  CAS  Google Scholar 

  2. Steinman, L. Elaborate interactions between the immune and nervous systems. Nat. Immunol. 5, 575–581 (2004).

    Article  CAS  Google Scholar 

  3. Jutel, M. et al. Histamine regulates T-cell and antibody responses by differential expression of H1 and H2 receptors. Nature 413, 420–425 (2001).

    Article  CAS  Google Scholar 

  4. Tracey, K.J. Reflex control of immunity. Nat. Rev. Immunol. 9, 418–428 (2009).

    Article  CAS  Google Scholar 

  5. Langrish, C.L. et al. IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J. Exp. Med. 201, 233–240 (2005).

    Article  CAS  Google Scholar 

  6. Ivanov, I.I. et al. The orphan nuclear receptor RORγt directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell 126, 1121–1133 (2006).

    Article  CAS  Google Scholar 

  7. Bettelli, E. et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 441, 235–238 (2006).

    Article  CAS  Google Scholar 

  8. Zhou, L., Chong, M.M. & Littman, D.R. Plasticity of CD4+ T cell lineage differentiation. Immunity 30, 646–655 (2009).

    Article  CAS  Google Scholar 

  9. Cua, D.J. et al. Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain. Nature 421, 744–748 (2003).

    Article  CAS  Google Scholar 

  10. Goverman, J. Autoimmune T cell responses in the central nervous system. Nat. Rev. Immunol. 9, 393–407 (2009).

    Article  CAS  Google Scholar 

  11. Axtell, R.C. et al. T helper type 1 and 17 cells determine efficacy of interferon-β in multiple sclerosis and experimental encephalomyelitis. Nat. Med. 16, 406–412 (2010).

    Article  CAS  Google Scholar 

  12. Centonze, D. et al. The link between inflammation, synaptic transmission and neurodegeneration in multiple sclerosis. Cell Death Differ. 17, 1083–1091 (2010).

    Article  CAS  Google Scholar 

  13. Pitt, D., Werner, P. & Raine, C.S. Glutamate excitotoxicity in a model of multiple sclerosis. Nat. Med. 6, 67–70 (2000).

    Article  CAS  Google Scholar 

  14. Besong, G. et al. Activation of group III metabotropic glutamate receptors inhibits the production of RANTES in glial cell cultures. J. Neurosci. 22, 5403–5411 (2002).

    Article  CAS  Google Scholar 

  15. Neufert, C. et al. IL-27 controls the development of inducible regulatory T cells and Th17 cells via differential effects on STAT1. Eur. J. Immunol. 37, 1809–1816 (2007).

    Article  CAS  Google Scholar 

  16. Batten, M. et al. Interleukin 27 limits autoimmune encephalomyelitis by suppressing the development of interleukin 17–producing T cells. Nat. Immunol. 7, 929–936 (2006).

    Article  CAS  Google Scholar 

  17. Schnurr, M. et al. Extracellular nucleotide signaling by P2 receptors inhibits IL-12 and enhances IL-23 expression in human dendritic cells: a novel role for the cAMP pathway. Blood 105, 1582–1589 (2005).

    Article  CAS  Google Scholar 

  18. Li, K. et al. Cyclic AMP plays a critical role in C3a-receptor–mediated regulation of dendritic cells in antigen uptake and T-cell stimulation. Blood 112, 5084–5094 (2008).

    Article  CAS  Google Scholar 

  19. Conn, P.J. & Pin, J.P. Pharmacology and functions of metabotropic glutamate receptors. Annu. Rev. Pharmacol. Toxicol. 37, 205–237 (1997).

    Article  CAS  Google Scholar 

  20. Maj, M. et al. (–)-PHCCC, a positive allosteric modulator of mGluR4: characterization, mechanism of action and neuroprotection. Neuropharmacology 45, 895–906 (2003).

    Article  CAS  Google Scholar 

  21. Zozulya, A.L., Clarkson, B.D., Ortler, S., Fabry, Z. & Wiendl, H. The role of dendritic cells in CNS autoimmunity. J. Mol. Med. 88, 535–544 (2010).

    Article  CAS  Google Scholar 

  22. Matute, C., Domercq, M. & Sanchez-Gomez, M.V. Glutamate-mediated glial injury: mechanisms and clinical importance. Glia 53, 212–224 (2006).

    Article  Google Scholar 

  23. McDonald, J.W., Althomsons, S.P., Hyrc, K.L., Choi, D.W. & Goldberg, M.P. Oligodendrocytes from forebrain are highly vulnerable to AMPA/kainate receptor–mediated excitotoxicity. Nat. Med. 4, 291–297 (1998).

    Article  CAS  Google Scholar 

  24. Stover, J.F. et al. Neurotransmitters in cerebrospinal fluid reflect pathological activity. Eur. J. Clin. Invest. 27, 1038–1043 (1997).

    Article  CAS  Google Scholar 

  25. Srinivasan, R., Sailasuta, N., Hurd, R., Nelson, S. & Pelletier, D. Evidence of elevated glutamate in multiple sclerosis using magnetic resonance spectroscopy at 3 T. Brain 128, 1016–1025 (2005).

    Article  Google Scholar 

  26. Newcombe, J. et al. Glutamate receptor expression in multiple sclerosis lesions. Brain Pathol. 18, 52–61 (2008).

    Article  Google Scholar 

  27. Pacheco, R. et al. Glutamate released by dendritic cells as a novel modulator of T cell activation. J. Immunol. 177, 6695–6704 (2006).

    Article  CAS  Google Scholar 

  28. Storto, M. et al. Expression of metabotropic glutamate receptors in murine thymocytes and thymic stromal cells. J. Neuroimmunol. 109, 112–120 (2000).

    Article  CAS  Google Scholar 

  29. Lock, C. et al. Gene-microarray analysis of multiple sclerosis lesions yields new targets validated in autoimmune encephalomyelitis. Nat. Med. 8, 500–508 (2002).

    Article  CAS  Google Scholar 

  30. Haak, S. et al. IL-17A and IL-17F do not contribute vitally to autoimmune neuro-inflammation in mice. J. Clin. Invest. 119, 61–69 (2009).

    CAS  Google Scholar 

  31. Segal, B.M. Th17 cells in autoimmune demyelinating disease. Semin. Immunopathol. 32, 71–77 (2010).

    Article  CAS  Google Scholar 

  32. Banchereau, J. & Steinman, R.M. Dendritic cells and the control of immunity. Nature 392, 245–252 (1998).

    Article  CAS  Google Scholar 

  33. Grohmann, U. et al. Functional plasticity of dendritic cell subsets as mediated by CD40 versus B7 activation. J. Immunol. 171, 2581–2587 (2003).

    Article  CAS  Google Scholar 

  34. Bhat, R. et al. Inhibitory role for GABA in autoimmune inflammation. Proc. Natl. Acad. Sci. USA 107, 2580–2585 (2010).

    Article  CAS  Google Scholar 

  35. Pampliega, O. et al. Association of an EAAT2 polymorphism with higher glutamate concentration in relapsing multiple sclerosis. J. Neuroimmunol. 195, 194–198 (2008).

    Article  CAS  Google Scholar 

  36. Conn, P.J., Christopoulos, A. & Lindsley, C.W. Allosteric modulators of GPCRs: a novel approach for the treatment of CNS disorders. Nat. Rev. Drug Discov. 8, 41–54 (2009).

    Article  CAS  Google Scholar 

  37. Pekhletski, R. et al. Impaired cerebellar synaptic plasticity and motor performance in mice lacking the mGluR4 subtype of metabotropic glutamate receptor. J. Neurosci. 16, 6364–6373 (1996).

    Article  CAS  Google Scholar 

  38. Fazio, F. et al. Switch in the expression of mGlu1 and mGlu5 metabotropic glutamate receptors in the cerebellum of mice developing experimental autoimmune encephalomyelitis and in autoptic cerebellar samples from patients with multiple sclerosis. Neuropharmacology 55, 491–499 (2008).

    Article  CAS  Google Scholar 

  39. Orabona, C. et al. Enhanced tryptophan catabolism in the absence of the molecular adapter DAP12. Eur. J. Immunol. 35, 3111–3118 (2005).

    Article  CAS  Google Scholar 

  40. Fallarino, F. et al. The combined effects of tryptophan starvation and tryptophan catabolites down-regulate T cell receptor ζ-chain and induce a regulatory phenotype in naive T cells. J. Immunol. 176, 6752–6761 (2006).

    Article  CAS  Google Scholar 

  41. Grohmann, U. et al. Reverse signaling through GITR ligand enables dexamethasone to activate IDO in allergy. Nat. Med. 13, 579–586 (2007).

    Article  CAS  Google Scholar 

  42. Romani, L. et al. Defective tryptophan catabolism underlies inflammation in mouse chronic granulomatous disease. Nature 451, 211–215 (2008).

    Article  CAS  Google Scholar 

  43. Grohmann, U. et al. CTLA-4–Ig regulates tryptophan catabolism in vivo. Nat. Immunol. 3, 1097–1101 (2002).

    Article  CAS  Google Scholar 

  44. Huang, Y.Y., Martin, K.C. & Kandel, E.R. Both protein kinase A and mitogen-activated protein kinase are required in the amygdala for the macromolecular synthesis–dependent late phase of long-term potentiation. J. Neurosci. 20, 6317–6325 (2000).

    Article  CAS  Google Scholar 

  45. Chen, T.C., Hinton, D.R., Zidovetzki, R. & Hofman, F.M. Up-regulation of the cAMP/PKA pathway inhibits proliferation, induces differentiation, and leads to apoptosis in malignant gliomas. Lab. Invest. 78, 165–174 (1998).

    CAS  PubMed  Google Scholar 

  46. Fallarino, F. et al. Therapy of experimental type 1 diabetes by isolated Sertoli cell xenografts alone. J. Exp. Med. 206, 2511–2526 (2009).

    Article  CAS  Google Scholar 

  47. Ngomba, R.T. et al. Positive allosteric modulation of metabotropic glutamate 4 (mGlu4) receptors enhances spontaneous and evoked absence seizures. Neuropharmacology 54, 344–354 (2008).

    Article  CAS  Google Scholar 

  48. Corti, C., Aldegheri, L., Somogyi, P. & Ferraguti, F. Distribution and synaptic localisation of the metabotropic glutamate receptor 4 (mGluR4) in the rodent CNS. Neuroscience 110, 403–420 (2002).

    Article  CAS  Google Scholar 

  49. Matrisciano, F. et al. Defective group-II metaboropic glutamate receptors in the hippocampus of spontaneously depressed rats. Neuropharmacology 55, 525–531 (2008).

    Article  CAS  Google Scholar 

  50. Bisognin, A. et al. A-MADMAN: annotation-based microarray data meta-analysis tool. BMC Bioinformatics 10, 201 (2009).

    Article  Google Scholar 

  51. Fleming, K.K. et al. Statistical analysis of data from studies on experimental autoimmune encephalomyelitis. J. Neuroimmunol. 170, 71–84 (2005).

    Article  CAS  Google Scholar 

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Acknowledgements

This work was supported by Fondazione Italiana Sclerosi Multipla Project No. 2008/R/2 (to G.B., U.G. and R.D.M.). We thank G. Andrielli for digital art and image editing, P. Scarselli for technical support and S. Iacobelli for statistical advice.

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Author notes

  1. Ferdinando Nicoletti, Ursula Grohmann and Roberto Di Marco: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Perugia, Italy

    Francesca Fallarino, Claudia Volpi, Carmine Vacca, Paolo Puccetti, Maria C Fioretti & Ursula Grohmann

  2. Istituto Neurologico Mediterraneo, Neuromed, Pozzilli, Italy

    Francesco Fazio, Serena Notartomaso, Carla Busceti, Giuseppe Battaglia, Valeria Bruno, Ferdinando Nicoletti & Roberto Di Marco

  3. Department of Health Sciences, University of Molise, Campobasso, Italy

    Serena Notartomaso & Roberto Di Marco

  4. Department of Biomedical Sciences, University of Modena and Reggio Emilia, Modena, Italy

    Silvio Bicciato

  5. Department of Human Physiology and Pharmacology, University of Rome 'La Sapienza', Rome, Italy

    Valeria Bruno & Ferdinando Nicoletti

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Contributions

F. Fallarino designed and performed experiments. C. Volpi, F. Fazio, S.N., C. Vacca and C.B. performed experiments. S.B. analyzed microarray data. G.B. and V.B. contributed to experiment design. P.P. and M.C.F. supervised research. F.N. contributed to experiment design and supervised research. R.D.M. designed experiments, supervised research and analyzed data. U.G. designed experiments, supervised research and wrote the manuscript.

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Correspondence to Ursula Grohmann.

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Fallarino, F., Volpi, C., Fazio, F. et al. Metabotropic glutamate receptor-4 modulates adaptive immunity and restrains neuroinflammation. Nat Med 16, 897–902 (2010). https://doi.org/10.1038/nm.2183

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