Novel Mechanism in Autoimmune Regulation by S-nitrosoglutathione

Abstract Nitric oxide (NO) plays a pivotal role in pathogenesis and control of autoimmune disease which is caused by abnormal activation of T helper (Th) cells. Under disease conditions of experimental autoimmune encephalomyelitis (EAE), we observed that different subsets of Th cells expressed different levels of NO synthesizing enzymes (nNOS, iNOS, and eNOS). Notably, Th17 cells exclusively expressed high levels of iNOS and its genetic ablation resulted in increased Th17 activation and IL-17 expression but decreased activation of specific subset of regulatory T (CD4+CD25+FOXP− Treg) cells and IL-10 expression in EAE. S-nitrosoglutathione (GSNO) is a physiological NO carrier molecules that mediates variety of NO signaling via trans-S-nitrosylation mechanisms. In EAE, GSNO treatment decreased the disease severity and activation/effector function of Th17 while it increased CD4+CD25+FOXP− Treg activation/effector function. Moreover, the reduced activation/effector function of Th17 by adaptive transfer of GSNO-induced CD4+CD25+FOXP− Tregs suggest that CD4+CD25+FOXP− Treg may be the effector cells antagonizing Th17 in response to iNOS/NO/GSNO. The cellular levels of GSNO is regulated by its catabolic enzyme GSNO reductase (GSNOR). In EAE, both Th17 and of CD4+CD25+FOXP− Treg expressed high levels of GSNOR and pharmacological inhibition of GSNOR or genetic ablation of GSNOR resulted in abrogation of Th17 activation/effector function while activating CD4+CD25+FOXP− Treg. In summary, this study suggest the iNOS/NO/GSNO-inducible CD4+CD25+FOXP− Treg cells as the potential feedback regulator of Th17 and GSNOR as the potential therapeutic target for Th17 and CD4+CD25+FOXP− Treg mediated autoimmune disease.