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S-nitrosoglutathione a Physiologic Nitric Oxide Carrier Attenuates Experimental Autoimmune Encephalomyelitis

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Abstract

S-nitrosoglutathione (GSNO) is a physiological nitric oxide molecule which regulates biological activities of target proteins via s-nitrosylation leading to attenuation of chronic inflammation. In this study we evaluated the therapeutic efficacy of GSNO in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. Oral administration of GSNO (0.5 or 1.0 mg/kg) reduced disease progression in chronic models (SJL and C57BL/6) of EAE induced with PLP(139–151) or MOG(35–55) peptides, respectively. GSNO attenuated EAE disease by reducing the production of IL17 (from Thi or Th17 cells) and the infiltration of CD4 T cells into the central nervous system without affecting the levels of Th1 (IFNγ) and Th2 (IL4) immune responses. Inhibition of IL17 was observed in T cells under normal as well as Th17 skewed conditions. In vitro studies showed that the phosphorylation of STAT3 and expression of RORγ, key regulators of IL17 signaling, were reduced while phosphorylation of STAT4 or STAT6 and expression of T-bet or GATA3 remained unaffected, suggesting that GSNO preferentially targets Th17 cells. Collectively, GSNO attenuated EAE via modulation of Th17 cells and its effects are independent of Th1 or Th2 cells functions, indicating that it may have therapeutic potential for Th17-mediated autoimmune diseases.

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References

  • Allione A, Bernabei P, Bosticardo M, Ariotti S, Forni G, Novelli F (1999) Nitric oxide suppresses human T lymphocyte proliferation through IFN-gamma-dependent and IFN-gamma-independent induction of apoptosis. J Immunol 163:4182–4191

    CAS  PubMed  Google Scholar 

  • Bauer H, Jung T, Tsikas D, Stichtenoth DO, Frolich JC, Neumann C (1997) Nitric oxide inhibits the secretion of T-helper 1- and T-helper 2-associated cytokines in activated human T cells. Immunology 90:205–211

    Article  CAS  PubMed  Google Scholar 

  • Becher B, Bechmann I, Greter M (2006) Antigen presentation in autoimmunity and CNS inflammation: how T lymphocytes recognize the brain. J Mol Med 84:532–543

    Article  CAS  PubMed  Google Scholar 

  • Bettelli E, Carrier Y, Gao W, Korn T, Strom TB, Oukka M, Weiner HL, Kuchroo VK (2006) Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 441:235–238

    Article  CAS  PubMed  Google Scholar 

  • Bogdan C (1998) The multiplex function of nitric oxide in (auto)immunity. J Exp Med 187:1361–1365

    Article  CAS  PubMed  Google Scholar 

  • Bogdan C (2001a) Nitric oxide and the immune response. Nat Immunol 2:907–916

    Article  CAS  PubMed  Google Scholar 

  • Bogdan C (2001b) Nitric oxide and the regulation of gene expression. Trends Cell Biol 11:66–75

    Article  CAS  PubMed  Google Scholar 

  • Chitnis T, Khoury SJ (2003) Cytokine shifts and tolerance in experimental autoimmune encephalomyelitis. Immunol Res 28:223–239

    Article  CAS  PubMed  Google Scholar 

  • Chiueh CC (1999) Neuroprotective properties of nitric oxide. Ann N Y Acad Sci 890:301–311

    Article  CAS  PubMed  Google Scholar 

  • Chiueh CC, Rauhala P (1999) The redox pathway of S-nitrosoglutathione, glutathione and nitric oxide in cell to neuron communications. Free Radic Res 31:641–650

    Article  CAS  PubMed  Google Scholar 

  • Cirino G, Fiorucci S, Sessa WC (2003) Endothelial nitric oxide synthase: the Cinderella of inflammation? Trends Pharmacol Sci 24:91–95

    Article  CAS  PubMed  Google Scholar 

  • Dalton DK, Wittmer S (2005) Nitric-oxide-dependent and independent mechanisms of protection from CNS inflammation during Th1-mediated autoimmunity: evidence from EAE in iNOS KO mice. J Neuroimmunol 160:110–121

    Article  CAS  PubMed  Google Scholar 

  • Dalton DK, Haynes L, Chu CQ, Swain SL, Wittmer S (2000) Interferon gamma eliminates responding CD4 T cells during mycobacterial infection by inducing apoptosis of activated CD4 T cells. J Exp Med 192:117–122

    Article  CAS  PubMed  Google Scholar 

  • Diefenbach A, Schindler H, Rollinghoff M, Yokoyama WM, Bogdan C (1999) Requirement for type 2 NO synthase for IL-12 signaling in innate immunity. Science 284:951–955

    Article  CAS  PubMed  Google Scholar 

  • Dong C (2008) TH17 cells in development: an updated view of their molecular identity and genetic programming. Nat Rev Immunol 8:337–348

    Article  CAS  PubMed  Google Scholar 

  • Fenyk-Melody JE, Garrison AE, Brunnert SR, Weidner JR, Shen F, Shelton BA, Mudgett JS (1998) Experimental autoimmune encephalomyelitis is exacerbated in mice lacking the NOS2 gene. J Immunol 160:2940–2946

    CAS  PubMed  Google Scholar 

  • Ferber IA, Brocke S, Taylor-Edwards C, Ridgway W, Dinisco C, Steinman L, Dalton D, Fathman CG (1996) Mice with a disrupted IFN-gamma gene are susceptible to the induction of experimental autoimmune encephalomyelitis (EAE). J Immunol 156:5–7

    CAS  PubMed  Google Scholar 

  • Fortenberry JD, Owens ML, Chen NX, Brown LA (2001) S-nitrosoglutathione inhibits TNF-alpha-induced NFkappaB activation in neutrophils. Inflamm Res 50:89–95

    Article  CAS  PubMed  Google Scholar 

  • Foster MW, McMahon TJ, Stamler JS (2003) S-nitrosylation in health and disease. Trends Mol Med 9:160–168

    Article  CAS  PubMed  Google Scholar 

  • Harrington LE, Hatton RD, Mangan PR, Turner H, Murphy TL, Murphy KM, Weaver CT (2005) Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nat Immunol 6:1123–1132

    Article  CAS  PubMed  Google Scholar 

  • Harris TJ, Grosso JF, Yen HR, Xin H, Kortylewski M, Albesiano E, Hipkiss EL, Getnet D, Goldberg MV, Maris CH, Housseau F, Yu H, Pardoll DM, Drake CG (2007) Cutting edge: an in vivo requirement for STAT3 signaling in TH17 development and TH17-dependent autoimmunity. J Immunol 179:4313–4317

    CAS  PubMed  Google Scholar 

  • Hendriks JJ, Teunissen CE, de Vries HE, Dijkstra CD (2005) Macrophages and neurodegeneration. Brain Res Brain Res Rev 48:185–195

    Article  CAS  PubMed  Google Scholar 

  • Hess DT, Matsumoto A, Kim SO, Marshall HE, Stamler JS (2005) Protein S-nitrosylation: purview and parameters. Nat Rev Mol Cell Biol 6:150–166

    Article  CAS  PubMed  Google Scholar 

  • Hoey S, Grabowski PS, Ralston SH, Forrester JV, Liversidge J (1997) Nitric oxide accelerates the onset and increases the severity of experimental autoimmune uveoretinitis through an IFN-gamma-dependent mechanism. J Immunol 159:5132–5142

    CAS  PubMed  Google Scholar 

  • Hogg N (1999) The kinetics of S-transnitrosation—a reversible second-order reaction. Anal Biochem 272:257–262

    Article  CAS  PubMed  Google Scholar 

  • Hogg N (2000) Biological chemistry and clinical potential of S-nitrosothiols. Free Radic Biol Med 28:1478–1486

    Article  CAS  PubMed  Google Scholar 

  • Hogg N (2002) The biochemistry and physiology of S-nitrosothiols. Annu Rev Pharmacol Toxicol 42:585–600

    Article  CAS  PubMed  Google Scholar 

  • Imitola J, Chitnis T, Khoury SJ (2005) Cytokines in multiple sclerosis: from bench to bedside. Pharmacol Ther 106:163–177

    Article  CAS  PubMed  Google Scholar 

  • Ivanov II, McKenzie BS, Zhou L, Tadokoro CE, Lepelley A, Lafaille JJ, Cua DJ, Littman DR (2006) The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell 126:1121–1133

    Article  CAS  PubMed  Google Scholar 

  • Izikson L, Klein RS, Luster AD, Weiner HL (2002) Targeting monocyte recruitment in CNS autoimmune disease. Clin Immunol 103:125–131

    Article  CAS  PubMed  Google Scholar 

  • Jourd’heuil D, Jourd’heuil FL, Feelisch M (2003) Oxidation and nitrosation of thiols at low micromolar exposure to nitric oxide. Evidence for a free radical mechanism. J Biol Chem 278:15720–15726

    Article  PubMed  CAS  Google Scholar 

  • Kahl KG, Schmidt HH, Jung S, Sherman P, Toyka KV, Zielasek J (2004) Experimental autoimmune encephalomyelitis in mice with a targeted deletion of the inducible nitric oxide synthase gene: increased T-helper 1 response. Neurosci Lett 358:58–62

    Article  CAS  PubMed  Google Scholar 

  • Khan M, Sekhon B, Giri S, Jatana M, Gilg AG, Ayasolla K, Elango C, Singh AK, Singh I (2005) S-Nitrosoglutathione reduces inflammation and protects brain against focal cerebral ischemia in a rat model of experimental stroke. J Cereb Blood Flow Metab 25:177–192

    Article  CAS  PubMed  Google Scholar 

  • Khan M, Jatana M, Elango C, Paintlia AS, Singh AK, Singh I (2006) Cerebrovascular protection by various nitric oxide donors in rats after experimental stroke. Nitric Oxide 15:114–124

    Article  CAS  PubMed  Google Scholar 

  • Kluge I, Gutteck-Amsler U, Zollinger M, Do KQ (1997) S-nitrosoglutathione in rat cerebellum: identification and quantification by liquid chromatography-mass spectrometry. J Neurochem 69:2599–2607

    Article  CAS  PubMed  Google Scholar 

  • Komiyama Y, Nakae S, Matsuki T, Nambu A, Ishigame H, Kakuta S, Sudo K, Iwakura Y (2006) IL-17 plays an important role in the development of experimental autoimmune encephalomyelitis. J Immunol 177:566–573

    CAS  PubMed  Google Scholar 

  • Kroenke MA, Carlson TJ, Andjelkovic AV, Segal BM (2008) IL-12- and IL-23-modulated T cells induce distinct types of EAE based on histology, CNS chemokine profile, and response to cytokine inhibition. J Exp Med 205:1535–1541

    Article  CAS  PubMed  Google Scholar 

  • Lander HM, Sehajpal P, Levine DM, Novogrodsky A (1993) Activation of human peripheral blood mononuclear cells by nitric oxide-generating compounds. J Immunol 150:1509–1516

    CAS  PubMed  Google Scholar 

  • Langrish CL, Chen Y, Blumenschein WM, Mattson J, Basham B, Sedgwick JD, McClanahan T, Kastelein RA, Cua DJ (2005) IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J Exp Med 201:233–240

    Article  CAS  PubMed  Google Scholar 

  • Li H, Forstermann U (2000) Nitric oxide in the pathogenesis of vascular disease. J Pathol 190:244–254

    Article  CAS  PubMed  Google Scholar 

  • Lipton SA, Choi YB, Pan ZH, Lei SZ, Chen HS, Sucher NJ, Loscalzo J, Singel DJ, Stamler JS (1993) A redox-based mechanism for the neuroprotective and neurodestructive effects of nitric oxide and related nitroso-compounds. Nature 364:626–632

    Article  CAS  PubMed  Google Scholar 

  • Mangan PR, Harrington LE, O’Quinn DB, Helms WS, Bullard DC, Elson CO, Hatton RD, Wahl SM, Schoeb TR, Weaver CT (2006) Transforming growth factor-beta induces development of the T(H)17 lineage. Nature 441:231–234

    Article  CAS  PubMed  Google Scholar 

  • Martinez-Ruiz A, Lamas S (2004) S-nitrosylation: a potential new paradigm in signal transduction. Cardiovasc Res 62:43–52

    Article  CAS  PubMed  Google Scholar 

  • McCartney-Francis N, Allen JB, Mizel DE, Albina JE, Xie QW, Nathan CF, Wahl SM (1993) Suppression of arthritis by an inhibitor of nitric oxide synthase. J Exp Med 178:749–754

    Article  CAS  PubMed  Google Scholar 

  • McGeachy MJ, Bak-Jensen KS, Chen Y, Tato CM, Blumenschein W, McClanahan T, Cua DJ (2007) TGF-beta and IL-6 drive the production of IL-17 and IL-10 by T cells and restrain T(H)-17 cell-mediated pathology. Nat Immunol 8:1390–1397

    Article  CAS  PubMed  Google Scholar 

  • Megson IL (2000) Nitric oxide donor drugs. Drugs Future 25:701–715

    Article  CAS  Google Scholar 

  • Mohr S, Zech B, Lapetina EG, Brune B (1997) Inhibition of caspase-3 by S-nitrosation and oxidation caused by nitric oxide. Biochem Biophys Res Commun 238:387–391

    Article  CAS  PubMed  Google Scholar 

  • Moilanen E, Vapaatalo H (1995) Nitric oxide in inflammation and immune response. Ann Med 27:359–367

    Article  CAS  PubMed  Google Scholar 

  • Murphy KM, Reiner SL (2002) The lineage decisions of helper T cells. Nat Rev Immunol 2:933–944

    Article  CAS  PubMed  Google Scholar 

  • Nath N, Prasad R, Giri S, Singh AK, Singh I (2006) T-bet is essential for the progression of experimental autoimmune encephalomyelitis. Immunology 118:384–391

    Article  CAS  PubMed  Google Scholar 

  • Niedbala W, Wei XQ, Piedrafita D, Xu D, Liew FY (1999) Effects of nitric oxide on the induction and differentiation of Th1 cells. Eur J Immunol 29:2498–2505

    Article  CAS  PubMed  Google Scholar 

  • Pannu R, Singh I (2006) Pharmacological strategies for the regulation of inducible nitric oxide synthase: neurodegenerative versus neuroprotective mechanisms. Neurochem Int 49:170–182

    Article  CAS  PubMed  Google Scholar 

  • Park H, Li Z, Yang XO, Chang SH, Nurieva R, Wang YH, Wang Y, Hood L, Zhu Z, Tian Q, Dong C (2005) A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat Immunol 6:1133–1141

    Article  CAS  PubMed  Google Scholar 

  • Prasad R, Giri S, Nath N, Singh I, Singh AK (2006) GSNO attenuates EAE disease by S-nitrosylation-mediated modulation of endothelial-monocyte interactions. Glia 55:65–77

    Article  Google Scholar 

  • Rauhala P, Lin AM, Chiueh CC (1998) Neuroprotection by S-nitrosoglutathione of brain dopamine neurons from oxidative stress. Faseb J 12:165–173

    CAS  PubMed  Google Scholar 

  • Schrammel A, Gorren AC, Schmidt K, Pfeiffer S, Mayer B (2003) S-nitrosation of glutathione by nitric oxide, peroxynitrite, and (*)NO/O(2)(*-). Free Radic Biol Med 34:1078–1088

    Article  CAS  PubMed  Google Scholar 

  • Segal BM (2003) Experimental autoimmune encephalomyelitis: cytokines, effector T cells, and antigen-presenting cells in a prototypical Th1-mediated autoimmune disease. Curr Allergy Asthma Rep 3:86–93

    Article  PubMed  Google Scholar 

  • Shi FD, Flodstrom M, Kim SH, Pakala S, Cleary M, Ljunggren HG, Sarvetnick N (2001) Control of the autoimmune response by type 2 nitric oxide synthase. J Immunol 167:3000–3006

    CAS  PubMed  Google Scholar 

  • Singh SP, Wishnok JS, Keshive M, Deen WM, Tannenbaum SR (1996) The chemistry of the S-nitrosoglutathione/glutathione system. Proc Natl Acad Sci USA 93:14428–14433

    Article  CAS  PubMed  Google Scholar 

  • Skundric DS (2005) Experimental models of relapsing-remitting multiple sclerosis: current concepts and perspective. Curr Neurovasc Res 2:349–362

    Article  CAS  PubMed  Google Scholar 

  • Sredni-Kenigsbuch D (2002) TH1/TH2 cytokines in the central nervous system. Int J Neurosci 112:665–703

    Article  PubMed  Google Scholar 

  • Stamler JS (1994) Redox signaling: nitrosylation and related target interactions of nitric oxide. Cell 78:931–936

    Article  CAS  PubMed  Google Scholar 

  • Tarrant TK, Silver PB, Wahlsten JL, Rizzo LV, Chan CC, Wiggert B, Caspi RR (1999) Interleukin 12 protects from a T helper type 1-mediated autoimmune disease, experimental autoimmune uveitis, through a mechanism involving interferon gamma, nitric oxide, and apoptosis. J Exp Med 189:219–230

    Article  CAS  PubMed  Google Scholar 

  • Taylor-Robinson AW, Liew FY, Severn A, Xu D, McSorley SJ, Garside P, Padron J, Phillips RS (1994) Regulation of the immune response by nitric oxide differentially produced by T helper type 1 and T helper type 2 cells. Eur J Immunol 24:980–984

    Article  CAS  PubMed  Google Scholar 

  • van der Veen RC (2001) Nitric oxide and T helper cell immunity. Int Immunopharmacol 1:1491–1500

    Article  PubMed  Google Scholar 

  • Weinberg JB, Granger DL, Pisetsky DS, Seldin MF, Misukonis MA, Mason SN, Pippen AM, Ruiz P, Wood ER, Gilkeson GS (1994) The role of nitric oxide in the pathogenesis of spontaneous murine autoimmune disease: increased nitric oxide production and nitric oxide synthase expression in MRL-lpr/lpr mice, and reduction of spontaneous glomerulonephritis and arthritis by orally administered NG-monomethyl-L-arginine. J Exp Med 179:651–660

    Article  CAS  PubMed  Google Scholar 

  • Williams MS, Noguchi S, Henkart PA, Osawa Y (1998) Nitric oxide synthase plays a signaling role in TCR-triggered apoptotic death. J Immunol 161:6526–6531

    CAS  PubMed  Google Scholar 

  • Wink DA, Darbyshire JF, Nims RW, Saavedra JE, Ford PC (1993) Reactions of the bioregulatory agent nitric oxide in oxygenated aqueous media: determination of the kinetics for oxidation and nitrosation by intermediates generated in the NO/O2 reaction. Chem Res Toxicol 6:23–27

    Article  CAS  PubMed  Google Scholar 

  • Wink DA, Nims RW, Darbyshire JF, Christodoulou D, Hanbauer I, Cox GW, Laval F, Laval J, Cook JA, Krishna MC et al (1994) Reaction kinetics for nitrosation of cysteine and glutathione in aerobic nitric oxide solutions at neutral pH. Insights into the fate and physiological effects of intermediates generated in the NO/O2 reaction. Chem Res Toxicol 7:519–525

    Article  CAS  PubMed  Google Scholar 

  • Wynn TA (2005) T(H)-17: a giant step from T(H)1 and T(H)2. Nat Immunol 6:1069–1070

    Article  CAS  PubMed  Google Scholar 

  • Yang XO, Panopoulos AD, Nurieva R, Chang SH, Wang D, Watowich SS, Dong C (2007) STAT3 regulates cytokine-mediated generation of inflammatory helper T cells. J Biol Chem 282:9358–9363

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We would like to thank Drs. Anne G. Gilg, Mushfiquddin Khan, Shailendra Giri, and Je-Seong Won for their constructive discussions and helpful suggestions; Dr. Jennifer G. Schnellmann for proofreading the manuscript; and Ms. Joyce Bryan, Ms Carrie Barnes, and Macela Rose for laboratory assistance.

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  1. Darby Children’s Research Institute, Medical University of South Carolina, 173 Ashley Avenue CRI # 505, Charleston, SC, 29425, USA

    Narender Nath & Inderjit Singh

  2. Department of Pharmacognosy, Nagasaki International University, Nagasaki, 859-3298, Japan

    Osamu Morinaga

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  1. Narender Nath
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Correspondence to Inderjit Singh.

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This work was supported in part by grants NS-22576, NS-34741, and NS-37766 from the National Institutes of Health.

Inderjit Singh and Narender Nath are guarantors of this work.

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Nath, N., Morinaga, O. & Singh, I. S-nitrosoglutathione a Physiologic Nitric Oxide Carrier Attenuates Experimental Autoimmune Encephalomyelitis. J Neuroimmune Pharmacol 5, 240–251 (2010). https://doi.org/10.1007/s11481-009-9187-x

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