S-nitrosoglutathione reductase (GSNOR) inhibitor as an immune modulator in experimental autoimmune encephalomyelitis

We previously reported that S-nitrosoglutathione (GSNO), an endogenous nitric oxide carrier, attenuated T_H17-mediated immune responses in experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis (MS). Cellular GSNO homeostasis is regulated via its synthesis by reaction between nitric oxide and glutathione and its enzymatic catabolism by GSNO reductase (GSNOR). In this study, we evaluated potential of reversible inhibitor of GSNOR (N6022) in comparison with exogenous GSNO in immunopathogenesis of EAE. Daily treatment of EAE mice with N6022 or exogenous GSNO significantly attenuated the clinical disease of EAE, but N6022 treatment showed greater efficacy than GSNO. Both N6022 and exogenous GSNO treatments increased the spleen levels of GSNO, as documented by increased protein-associated S-nitrosothiols, and inhibited polarization and CNS effector function of proinflammatory T_H17 cells while inducing the polarization and CNS effector function of anti-inflammatory CD4⁺ CD25⁺ FOXP3^- regulatory T (Treg) cells. Moreover, N6022 further attenuated T_H1 while inducing T_H2 and CD4⁺ CD25⁺ FOXP3⁺ Treg in their polarization and CNS effector functions. Similar to GSNO, the N6022 treatment protected against the EAE disease induced demyelination. However, neither exogenous GSNO nor N6022 treatment did not cause significant systemic lymphopenic effect as compared to FTY720. Taken together, these data document that optimization of cellular GSNO homeostasis by GSNOR inhibitor (N6022) in NO metabolizing cells attenuates EAE disease via selective inhibition of pro-inflammatory subsets of CD4⁺ cells (T_H1/T_H17) while upregulating anti-inflammatory subsets of CD4⁺ cells (T_H2/Treg) without causing lymphopenic effects and thus offers a potential treatment option for MS/EAE.