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    • Decreased ratio of Treg TH is reported

    2022-07-04

    Decreased ratio of Treg/TH17 is reported to correlate with MS disease severity [63]. Treg f4 cat mg are the major anti-inflammatory subset of T cells which suppress proinflammatory T-cells by producing anti-inflammatory cytokines, such as IL-10 and TGF-β, as well as play a critical role in maintaining tolerance to self-antigens and thus preventing autoimmune disease [15], [64], [65]. CD4+ CD25+Treg cells are divided into two subgroups beased on their expression of FOXP3; FOXP3+ Tregs (nTreg and iTreg) and FOXP3- Tregs (NO-Treg and Tr1) [23], [56], [57]. In this study, we observed that GSNO treatment had no effect on polarization and CNS effector function of FOXP3+Tregs under EAE conditions (Figs. 1C and 2B), however, it sginificantly increased the polarization and CNS effector functions of FOXP3- Tregs (Figs. 1C and 2B). In consistent with our observation, previous studies reported that treatment of CD4+CD25− T cells with diazeniumdiolate (NONOate, a NO donor) induces polarization and effector function (IL-10 production) of CD4+/CD25+/FOXP3- Tregs, named, ‘NO-Treg’ [23]. Subsequently, the same research group reported that these NO-inducible CD4+/CD25+/FOXP3- Tregs inhibits TH17, but not TH1, while CD4+/CD25+/FOXP3+Tregs (nTreg and iTreg) inhibit TH1 [24]. Taken together with our previous studies documenting the role of GSNO in inhibition of STAT3 [22], [49], [60], [66], these studies document the role of GSNO mediated mechanisms in inhibition of TH17-mediated proinflammatory processes directly by inhibiting STAT3 as well as via GSNO mediated induction of CD4+/CD25+/FOXP3- Tregs (NO-Tregs). GSNO exerts its biological effects by protein modifications via S-nitrosylation, a reversible and specific post-translational modification that regulates activities of large number of target proteins and thus various cellular activities and functions [26]. The cellular synthesis of GSNO is mediated by reaction between NOS and GSH in the presence of electron acceptors or formation of transition metal adduct [67]. Therefore, cell/tissue specific expression and activity of NOS and maintenance of redox potential (GSH) are important for cellular GSNO homeostasis. GSNO is catabolized by GSNOR, a class III alcohol dehydrogenase (ADH), and thus cell/tissue specific regulation of GSNOR in its expression and activity is also important for cellular GSNO homeostasis. At present, the mechanisms underlying the regulation of GSNOR is not well understood, but NFκB mediated regulation of its transcription [68] and GSNO-mediated feed-forward induction of its activity [69] have been reported. Based on the importance of GSNOR in cellular GSNO homeostasis, next, we evaluated the efficacy of endogenous GSNO using N6022, a first-in-class inhibitor of GSNO catabolizing enzyme GSNOR in EAE disease. GSNOR inhibitors are being tested for clinical use for asthma and cystic fibrosis [70]. Among these, N6022 is the best characterized and its safety was proven by Phase I and II studies [50]. In this study, we observed that N6022 treatment of EAE mice attenuated the progression of EAE disease efficiently. Similar to GSNO studies, EAE mice treated with N6022 also showed decreased polarization and effector function of TH17 cells and increased polarization and effector function of CD4+/CD25+/FOXP3- Tregs (Figs. 5B, C, 6B, and C). Moreover, N6022 treatment, but not GSNO treatment, also attenuated TH1, while increasing TH2 and CD4+/CD25+/FOXP3+ Treg, in polarizations and their effector functions in EAE mice (Figs. 5B, C, 6B and C). Although GSNO and N6022 treatments produced differential effects on these polarizations in spleens of EAE mice (Fig. 5, Fig. 6) but both treatments increased comparable levels of protein-associated S-nitrosolthiols in the spleen (Fig. 4). Cellular PrSNOs are known to be in transnitrosation equilibrium with GSNO [59], indicating that the observed increases in PrSNO levels reflect increased levels of GSNO in the spleens of GSNO and N6022 treated mice. At present, mechanisms underlyng the differential effects of GSNO and N6022 on the polarization of different subsets of CD4+ T cells is not understood. Logically, exogenous GSNO treatment is expected to distribute all over the body but cell specific accumulation of exogenous GSNO levels depends on cell specific activity of GSNOR. On the other hand, N6022 treatment is expected to elevate GSNO levels more in the cells with higher GSNO dynamics as high GSNO synthesis (NOS expressing cells) and degradation (GSNOR expressing cells). Therefore, even though exogenous GSNO and endogenous GSNO (N6022 treatment) increased near comparable levels of PrSNOs (GSNO) in the spleens of EAE mice, their cell type specific effects may be different in GSNO or GSNOR inhibitor treated mice. It should be of interest to evaluate the NO metabolome mediated regulation of different subset of CD4+ T cells.