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  • Introduction Multiple sclerosis MS a neurological autoimmune

    2022-07-01

    Introduction Multiple sclerosis (MS), a neurological autoimmune disease, is driven by CD4+ ruthenium red australia of the T helper (TH) cells [1]. There is no curative treatment for MS and the present treatments typically focus on immunomodulation for slowing the progression of the disease. These includes interferon-β (IFN-β), a naturally occurring anti-inflammatory polypeptide [2], glatiramer acetate, a synthetic peptides inducing anti-inflammatory TH2 responses [3], teriflunomide, a cell proliferation inhibitor [4], dimethyl fumarate, an immunomodulatory agent with unknown mechanism [5], natalizumab, a monoclonal antibody against α4-integrin blocking immune cell infiltration [6], fingolimod (FTY720), an oral sphingosine 1-phosphate receptor modulator inhibiting lymphocyte egress from the lymph nodes to the CNS [7], alemtuzumab, a recombinant monoclonal antibody against CD52 on T and B lymphocytes [8], and mitoxantrone, a compound inhibiting DNA synthesis and thus lymphocyte proliferation [9]. These drugs, in general, are non-specific immune-modulating agents and thus increase the risk for infectious diseases by weakening the global immune system. In addition, some of peptide- or antibody-based drugs could develop autoantibody and thus may increase the risk for autoimmune-mediated conditions while chemotherapy based drugs may cause various adverse effects by killing healthy dividing cells [10]. Moreover, in spite of the immune modulating activities, these drugs do not protect against the CNS disease of MS as the CNS disease progression continues with the medications. These observations underscore the new class of drugs targeting MS specific proinflammatory autoimmune responses, as well as protection against the CNS disease progression. MS and experimental autoimmune encephalomyelitis (EAE; an animal model for MS) are mediated by activation and CNS infiltration of myelin specific autoreactive CD4+ T cells. TH1 and TH17 cells are the major subsets of proinflammatory CD4+ T cells mediating the CNS inflammation and thus demyelination via production of proinflammatory cytokines, such as IFN-γ and IL-17 [11]. Development and function of TH1 and TH17 cells are regulated by TH2 and regulatory T (Treg) cells [12], [13], [14]. Accordingly, TH2 and Treg cells are considered as anti-inflammatory subset of CD4+ T cells in EAE and MS [15], [16]. MS patients are known to have decreased number of Treg cells at the site of local inflammation in the CNS [17], [18]. Treg cells are the major cellular source of IL-10 and TGF-β that play critical roles in immuno-tolerance and also suppression of proinflammatory T-cells [15]. Therefore, modulation of subset specific autoimmune responses (TH1/TH17 vs. TH2/Treg), rather than suppression of global immune system, is critical for efficient control of disease with minimizing the unnecessary inhibition of systemic immune surveillance. There is a growing body of evidence that nitric oxide (NO) plays an important role in regulation of cellular processes involved in immune and inflammatory responses [19]. Cellular NO is synthesized by three distinct forms of NO synthases (NOS): neuronal NOS (nNOS), inducible NOS (iNOS), and endothelial NOS (eNOS) [20]. NO is reported to play an important role in inhibition of differentiation of TH17 cells and their effector function, such as release of IL-17 [21], [22]. Accordingly, genetic ablation of iNOS, but not nNOS and eNOS, increased the severity of EAE disease via inducing TH17 cells [21]. NO was also reported to induce a specific subset of CD4+/CD25+/FOXP3- Treg cells, called NO-Treg, that attenuate EAE disease via inducing the release of IL-10 and thus inhibition of TH17 cells [23], [24]. NO exerts its biological functions by direct activation of soluble guanylyl cyclase (sGC) and thus activation of cGMP/PKG pathway or via formation of secondary redox intermediates, peroxynitrite (ONOO-) and S-nitrosoglutathione (GSNO). ONOO- is synthesized by reaction between NO and superoxide anion (O2•ˉ) under pathological conditions. ONOOˉ is the most powerful oxidative/nitrosative agent and its deleterious role in MS/EAE pathology has been widely reported by various investigators [see review [25]]. GSNO is the most abundant low-molecular-weight S-nitrosothiol, a biological NO carrier, which is synthesized by reaction between NO and glutathione (GSH) [26]. GSNO does not release free NO [27], rather, it exerts its biological activity via secondary modification of protein thiols, a process termed S-nitrosylation [26]. At present, over 3000 proteins, which regulate various cellular functions, are identified to be S-nitrosylated [28]. Similar to the role of ONOOˉ, over accumulations of cellular GSNO and S-nitrosylated proteins (PrSNO) under pathological conditions with the presence of transition metals or GSNO reductase (GSNOR/ADH5) deficient conditions is reported to be harmful for neural and immunological functions [29], [30], [31]. However, physiological levels of GSNO/PrSNO are implicated in regulation of various cellular processes for cardiovascular hemodynamics [32], redox balance [33], [34], and inflammatory processes [35], [36]. In addition, the reported beneficial effect of exogenous GSNO treatment in various neurological, cardiovascular, infectious, and immune disease models [22], [36], [37], [38], [39], [40], [41], [42], [43], [44], [45], [46] suggest the pathophysiological importance of GSNO-mediated cellular mechanisms.