S-nitrosoglutathione a physiologic nitric oxide carrier attenuates experimental autoimmune encephalomyelitis

J Neuroimmune Pharmacol. 2010 Jun;5(2):240-51. doi: 10.1007/s11481-009-9187-x. Epub 2010 Jan 21.

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 Th(i) or Th17 cells) and the infiltration of CD4 T cells into the central nervous system without affecting the levels of Th1 (IFN gamma) 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 ROR gamma, 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.

MeSH terms

  • Animals
  • Blotting, Western
  • CD4-Positive T-Lymphocytes / drug effects
  • Cell Differentiation / drug effects
  • Encephalomyelitis, Autoimmune, Experimental / drug therapy*
  • Female
  • GATA3 Transcription Factor / metabolism
  • Glycoproteins / immunology
  • Interleukin-17 / biosynthesis
  • Mice
  • Mice, Inbred C57BL
  • Myelin Proteolipid Protein / immunology
  • Myelin-Oligodendrocyte Glycoprotein
  • Nitric Oxide Donors / therapeutic use*
  • Nuclear Receptor Subfamily 1, Group F, Member 3 / biosynthesis
  • Peptide Fragments / immunology
  • Phosphorylation
  • S-Nitrosoglutathione / therapeutic use*
  • STAT Transcription Factors / genetics
  • STAT Transcription Factors / metabolism
  • Spinal Cord / pathology
  • Th1 Cells / immunology
  • Th2 Cells / immunology

Substances

  • GATA3 Transcription Factor
  • Gata3 protein, mouse
  • Glycoproteins
  • Interleukin-17
  • Myelin Proteolipid Protein
  • Myelin-Oligodendrocyte Glycoprotein
  • Nitric Oxide Donors
  • Nuclear Receptor Subfamily 1, Group F, Member 3
  • Peptide Fragments
  • Rorc protein, mouse
  • STAT Transcription Factors
  • myelin oligodendrocyte glycoprotein (35-55)
  • myelin proteolipid protein (139-151)
  • S-Nitrosoglutathione