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Metabotropic Glutamate Receptor-4 Modulates Adaptive Immunity and Restrains Neuroinflammation

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Metabotropic Glutamate Receptor-4 Modulates Adaptive Immunity and Restrains Neuroinflammation ARTICLES Metabotropic glutamate receptor-4 modulates adaptive immunity and restrains neuroinflammation Francesca Fallarino1, Claudia Volpi1, Francesco Fazio2, Serena Notartomaso2,3, Carmine Vacca1, Carla Busceti2, Silvio Bicciato4, Giuseppe Battaglia2, Valeria Bruno2,5, Paolo Puccetti1, Maria C Fioretti1, Ferdinando Nicoletti2,5,6, Ursula Grohmann1,6 & Roberto Di Marco2,3,6 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. Classical neurotransmitters such as monoamines and acetylcholine mGluR8, which are also coupled to Gi and Go proteins in heterologous regulate the magnitude and quality of immune responses1–4. The expression systems (further detailed in Supplementary Note). recent discovery of interleukin-17 (IL-17)-producing TH17 cells Although inflammatory cytokines and glutamate are thought to con- as a distinct subset of effector cells has provided new insight into tribute to neurodegeneration in multiple sclerosis as well as in EAE, 5,6 the intricacies of immunopathology . TH17 cells have key roles early alterations of the neuronal compartment occurring in this disor- in inflammation and autoimmunity5,7 and develop under strict, der are partially independent of demyelination. How immune cells and 7,8 bidirectional influence by Treg cells . Although TH17 cells act soluble cytokines are connected temporally and causally with synaptic as mediators of autoimmunity in EAE and multiple sclerosis5,9, transmission and neurodegeneration remains elusive12. In EAE, adminis- © 2010 Nature America, Inc. All rights reserved. All rights Inc. America, Nature © 2010 several reports raise the question of whether TH1 or TH17 cells are tration of an iGluR antagonist increases oligodendrocyte survival but does the predominant pathogenic T cells. There is growing evidence that not reduce neuroinflammation13. Conversely, l-2-amino-4-phosphono- clinically similar forms of autoimmune demyelinating disease can butanoate (l-AP4), an orthosteric agonist specific for group III be driven by myelin-specific T cells of distinct lineages with vary- mGluRs, increases recovery rate in Lewis rats with EAE14. ing degrees of dependence on IL-17A production to achieve their pathological effects10. A recent report suggests that interferon-β is RESULTS effective in reducing EAE sustained by TH1 cells but exacerbates EAE is exacerbated by mGluR4 deficiency 11 −/− disease by TH17 cells . mGluR4-knockout (Grm4 ) mice and their wild-type (WT) Glutamate, the major excitatory neurotransmitter in the central counterparts were immunized with myelin oligodendrocyte glyco- nervous system (CNS), activates ligand-gated ion channels (iono- protein (MOG35–55), and EAE clinical scores were recorded daily over tropic glutamate receptors; iGluRs) as well as G-protein coupled a period of 40 d. A lack of mGluR4 was associated with earlier onset receptors (metabotropic glutamate receptors or mGluRs). mGluRs (P < 0.005), as well as more severe (P < 0.05) and ultimately fatal form a family of eight subtypes, subdivided into three groups on the disease in >40% of the hosts (Fig. 1a and Supplementary Table 1). basis of their amino acid sequence and G-protein coupling. Group I Morphologically, white matter demyelination and inflammatory includes mGluR1 and mGluR5, which are coupled to Gq protein; infiltrates were more prevalent in the spinal cord of MOG-vaccinated group II includes mGluR2 and mGluR3, which are coupled to Grm4−/− mice than in WT mice (Fig. 1b). EAE was associated with + + + Gi and Go proteins; group III includes mGluR4, mGluR6, mGluR7 and infiltration of CD4 , CD8 and B220 cells from peripheral lymphoid 1Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Perugia, Italy. 2Istituto Neurologico Mediterraneo, Neuromed, Pozzilli, Italy. 3Department of Health Sciences, University of Molise, Campobasso, Italy. 4Department of Biomedical Sciences, University of Modena and Reggio Emilia, Modena, Italy. 5Department of Human Physiology and Pharmacology, University of Rome ‘La Sapienza’, Rome, Italy. 6These authors contributed equally to this work. Correspondence should be addressed to U.G. ([email protected]). Received 27 January; accepted 21 June; published online 25 July 2010; doi:10.1038/nm.2183 NATURE MEDICINE VOLUME 16 | NUMBER 8 | AUGUST 2010 897 A RTICLES WT Grm4–/– Figure 1 mGluR4-deficient mice are highly susceptible to EAE. Active EAE was a b −/− –/– induced in WT and mice by immunization with the MOG peptide. 5 Grm4 Grm4 (a) Clinical EAE scores (means ± s.d.) over time and linear regression analysis. 4 WT P P < 0.001 Data are from one experiment representative of three, which is also referred 3 MB to as ‘Exp. No. 2’ in Supplementary Table 1. (b) Histopathological analysis 2 100 µm of spinal cord sections from representative WT and Grm4−/− mice at 30 d 1 after immunization. Spinal cord sections were stained with H&E to assess Mean clinical score 0 inflammation and immunostained for myelin-binding protein (MBP) to evaluate H&E 0 5 10 15 20 25 30 35 40 45 myelin depletion. Arrows indicate demyelinated areas and inflammatory cellular 50 µm Time (d) after immunization infiltrates in MBP and H&E immunostaining, respectively. organs to the CNS in both Grm4−/− and WT mice, but the percentages we did not observe any Grm6 transcripts in any of the examined cell of CD4+ and CD8+ T cells—as well as CD11b+ and CD11c+ cells— types, including brain tissue (data not shown and Supplementary were markedly higher in the CNS of Grm4−/− mice at the peak of Note), peculiar expression patterns characterized the other genes. In disease (Supplementary Table 2 and Supplementary Figs. 1–3). particular, Grm4 expression was highest in CD4+ and CD11c+ cells, When we extended our analysis to littermates from heterozygote establishing those cells as potential targets for mGluR4-mediated + − breeding—with cohorts of mice being matched for gender and age— effects. Activation of CD4 CD25 cells under TH0-, TH1- and induc- −/− +/− the disease course was also more severe in Grm4 and Grm4 mice ible Treg (iTreg)-favoring conditions led to substantial Grm4 upregu- +/+ than in Grm4 mice (Supplementary Fig. 4). lation, whereas we observed no effect in a TH2-biased environment. Grm4 expression was also upregulated in activated natural Treg EAE cytokine profile is affected by mGluR4 signaling (nTreg) cells (Fig. 3b) as well as in iTreg cells (data not shown). Gene −/− We evaluated the cytokine profile in Grm4 relative to WT mice expression was virtually absent in a TH17-biased setting (Fig. 3b). after MOG vaccination. In sorted CD4+ T cells from brain-infiltrating leukocytes (BILs), we found a significant increase in Rorc transcripts a 10 d 30 d 30 d 10 (encoding the TH17 specification factor), a reduction in Foxp3 (Treg) ** ** WT transcripts, and no change in Tbx21 (coding for Tbet; a T 1 marker) e –/– H 8 Grm4–/– Grm4 in Grm4−/− mice at the peak of neurologic signs (30 d after immuniza- 6 ** WT tion; Fig. 2a). A similar pattern was evident earlier (at 10 d) in CD4+ * 4 T cells sorted from pooled lymph nodes of mGluR4-deficient mice Foxp3 2 (Fig. 2a). No change occurred in Gata3 (a TH2 marker) in any groups mRNA fold chang (Fig. 2a). It seems that the absence of mGluR4 tipped the balance of 0 transcriptional activation in favor of inflammatory genes in response Tbx21 Gata3 Rorc Foxp3 Tbx21 Gata3 Rorc Foxp3Tbx21 Gata3 Rorc Foxp3 to MOG vaccination. LN BIL The cytokine profile in mice with EAE (high IL-17A and low Control MOG b LN ) ** ) ) transforming growth factor-β (TGF-β) from T cells and high IL-6 ) –1 ** –1 0.8 –1 –1 4 4 4 ** ** and low IL-27 from DCs) suggested that the lack of mGluR4 3 ** 3 3 ** ** 0.6 ** ** (ng ml 0.4 favored the emergence of T 17 over T cells, which would sustain 2 2 ** (ng ml 2 β H reg γ inflammation and exacerbate clinical signs of EAE (Fig. 2b,c and 1 1 1 0.2 IL-10 (ng ml IFN- © 2010 Nature America, Inc. All rights reserved. All rights Inc. America, Nature © 2010 TGF- 0 IL-17A (ng ml 0 0 0 Supplementary Results). WT Grm4 –/– WT Grm4 –/– WT Grm4 –/– WT Grm4 –/– + Grm4 is expressed in accessory and adaptive immune cells CD11c cells Control MOG-vaccinated ) ) ) –1 0.4 –1 0.4 0.4 Expression of Grm4, Grm6, Grm7 and Grm8 was examined by –1 0.3 0.3 0.3 real-time RT-PCR (rRT-PCR) in WT brain cells, lymph node cells ** ** ** ** ** 0.2 * 0.2 0.2 and total splenocytes in addition to specifically sorted cell types 0.1 0.1 0.1 IL-6 (ng ml IL-12 (ng ml + + + + + IL-10 (ng ml (CD4 , CD8 , γδ, B220 , CD11b and CD11c ; Fig. 3a). Although 0 0 0 ) ) ) –1 –1 0.8 0.8 –1 ** ** Figure 2 mGluR4 deficiency alters T cell differentiation and cytokine ** 30 H 0.6 0.6 ** production. Active EAE was induced in WT and Grm4−/− mice as in Figure 1. ** 20 (ng ml ** ** 0.4 β 0.4 (a) Tbx21, Gata3, Rorc and Foxp3 transcript levels in CD4+ T cells sorted 0.2 0.2 10 IL-23 (ng ml IL-27 (pg ml from BILs at 30 d post-MOG vaccination and from lymph node (LN) cells at TGF- 0 0 0 10 and 30 d by rRT-PCR, using Gapdh (encoding glyceraldehyde 3-phosphate WT Grm4 –/– WT Grm4 –/– WT Grm4 –/– dehydrogenase) for normalization.
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