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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Woiciechowsky, C. et al. Sympathetic activation triggers systemic interleukin-10 release in immunodepression induced by brain injury. Nat. Med. 4, 808–813 (1998).
Steinman, L. Elaborate interactions between the immune and nervous systems. Nat. Immunol. 5, 575–581 (2004).
Jutel, M. et al. Histamine regulates T-cell and antibody responses by differential expression of H1 and H2 receptors. Nature 413, 420–425 (2001).
Tracey, K.J. Reflex control of immunity. Nat. Rev. Immunol. 9, 418–428 (2009).
Langrish, C.L. et al. IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J. Exp. Med. 201, 233–240 (2005).
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).
Bettelli, E. et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 441, 235–238 (2006).
Zhou, L., Chong, M.M. & Littman, D.R. Plasticity of CD4+ T cell lineage differentiation. Immunity 30, 646–655 (2009).
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).
Goverman, J. Autoimmune T cell responses in the central nervous system. Nat. Rev. Immunol. 9, 393–407 (2009).
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).
Centonze, D. et al. The link between inflammation, synaptic transmission and neurodegeneration in multiple sclerosis. Cell Death Differ. 17, 1083–1091 (2010).
Pitt, D., Werner, P. & Raine, C.S. Glutamate excitotoxicity in a model of multiple sclerosis. Nat. Med. 6, 67–70 (2000).
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).
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).
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).
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).
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).
Conn, P.J. & Pin, J.P. Pharmacology and functions of metabotropic glutamate receptors. Annu. Rev. Pharmacol. Toxicol. 37, 205–237 (1997).
Maj, M. et al. (–)-PHCCC, a positive allosteric modulator of mGluR4: characterization, mechanism of action and neuroprotection. Neuropharmacology 45, 895–906 (2003).
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).
Matute, C., Domercq, M. & Sanchez-Gomez, M.V. Glutamate-mediated glial injury: mechanisms and clinical importance. Glia 53, 212–224 (2006).
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).
Stover, J.F. et al. Neurotransmitters in cerebrospinal fluid reflect pathological activity. Eur. J. Clin. Invest. 27, 1038–1043 (1997).
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).
Newcombe, J. et al. Glutamate receptor expression in multiple sclerosis lesions. Brain Pathol. 18, 52–61 (2008).
Pacheco, R. et al. Glutamate released by dendritic cells as a novel modulator of T cell activation. J. Immunol. 177, 6695–6704 (2006).
Storto, M. et al. Expression of metabotropic glutamate receptors in murine thymocytes and thymic stromal cells. J. Neuroimmunol. 109, 112–120 (2000).
Lock, C. et al. Gene-microarray analysis of multiple sclerosis lesions yields new targets validated in autoimmune encephalomyelitis. Nat. Med. 8, 500–508 (2002).
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).
Segal, B.M. Th17 cells in autoimmune demyelinating disease. Semin. Immunopathol. 32, 71–77 (2010).
Banchereau, J. & Steinman, R.M. Dendritic cells and the control of immunity. Nature 392, 245–252 (1998).
Grohmann, U. et al. Functional plasticity of dendritic cell subsets as mediated by CD40 versus B7 activation. J. Immunol. 171, 2581–2587 (2003).
Bhat, R. et al. Inhibitory role for GABA in autoimmune inflammation. Proc. Natl. Acad. Sci. USA 107, 2580–2585 (2010).
Pampliega, O. et al. Association of an EAAT2 polymorphism with higher glutamate concentration in relapsing multiple sclerosis. J. Neuroimmunol. 195, 194–198 (2008).
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).
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).
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).
Orabona, C. et al. Enhanced tryptophan catabolism in the absence of the molecular adapter DAP12. Eur. J. Immunol. 35, 3111–3118 (2005).
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).
Grohmann, U. et al. Reverse signaling through GITR ligand enables dexamethasone to activate IDO in allergy. Nat. Med. 13, 579–586 (2007).
Romani, L. et al. Defective tryptophan catabolism underlies inflammation in mouse chronic granulomatous disease. Nature 451, 211–215 (2008).
Grohmann, U. et al. CTLA-4–Ig regulates tryptophan catabolism in vivo. Nat. Immunol. 3, 1097–1101 (2002).
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).
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).
Fallarino, F. et al. Therapy of experimental type 1 diabetes by isolated Sertoli cell xenografts alone. J. Exp. Med. 206, 2511–2526 (2009).
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).
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).
Matrisciano, F. et al. Defective group-II metaboropic glutamate receptors in the hippocampus of spontaneously depressed rats. Neuropharmacology 55, 525–531 (2008).
Bisognin, A. et al. A-MADMAN: annotation-based microarray data meta-analysis tool. BMC Bioinformatics 10, 201 (2009).
Fleming, K.K. et al. Statistical analysis of data from studies on experimental autoimmune encephalomyelitis. J. Neuroimmunol. 170, 71–84 (2005).
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.
The authors declare no competing financial interests.
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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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