Potential Role of Nitrobiolome in Autoimmune Disease: Efficacy of GSNO in EAE.

Abstract

Abstract S-nitrosoglutathione (GSNO) is a physiological nitric oxide (NO) carrier molecule important in modulation of NO-signaling. Cellular GSNO homeostasis is maintained by its synthesis by nitric oxide synthase (NOS) as well as its catabolism by GSNO reductase (GSNOR). Treatment of EAE mice (wild-type /WT) with exogenous GSNO or GSNOR inhibitor (N6022) significantly alleviated the clinical disease and associated myelin damage. In addition, more profound alleviation of EAE disease was observed in mice deficient in GSNOR (GSNOR−/−). However, EAE disease was further exacerbated in mice deficient in inducible NOS (iNOS−/−) as compared to WT mice. As expected, the spleen levels of S-nitrosothiol proteins were higher in GSNOR−/− EAE mice but lower in iNOS−/− EAE mice compared to WT EAE mice indicating a negative correlation of spleen GSNO levels with EAE disease severities. Both GSNO and N6022 treated EAE mice had decreased TH17 and increased CD4+/CD25+/FOXP3− Treg differentiations without any significant alterations in other CD4+ T cell subset differentiation. Accordingly, CD4 T+ cells from GSNO or N6022 treated EAE mice produced lower amount of IL-17 and higher amount of IL-10 compared to the cells from untreated WT EAE mice. GSNOR−/− EAE mice also exhibited decreased T 17 and increased CD4+/CD25+/FOXP3− Treg differentiations. On the other hand, iNOS−/− EAE mice exhibited increased TH17, but decreased Tregs differentiations compared to WT EAE mice. In summary, these studies document that nitrobiolome (GSNO) participates in differentiation of autoreactive TH17 and Treg subsets during the course of EAE, and that GSNO as a potential therapeutic drug for multiple sclerosis. Supported in-part by VA(BX002829) and NIH(NS037766).