Metabotropic glutamate receptor-4 modulates adaptive immunity and restrains neuroinflammation

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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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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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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The authors declare no competing financial interests.

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Supplementary Figures 1–17, Supplementary Tables 1–7, Supplementary Results, Supplementary Note and Supplementary Methods (PDF 1302 kb)

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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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