Therapeutic potential of S-nitrosoglutathione reductase inhibitor in B cell-driven experimental autoimmune encephalomyelitis

We previously reported that S-nitrosoglutathione (GSNO) and GSNO reductase inhibitors, which increase endogenous GSNO, mitigate T cell-dependent experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis, by suppressing Th1 and Th17 effector T cells while promoting regulatory T cells (Tregs). In this study, we demonstrate that the GSNO reductase inhibitor (N6022) also alleviates B cell-dependent EAE in C57BL/6 mice immunized with recombinant human myelin oligodendrocyte glycoprotein (rhMOG₁_-₁₂₅). Daily N6022 treatment following disease onset significantly reduced clinical EAE disease symptoms. N6022 treatment increased the number of CD1d^hiCD5⁺ regulatory B cells (Bregs) in the spleen and inhibited B cell expression of the effector cytokine IL-6 while enhancing their expression of the regulatory cytokine IL-10. Accordingly, N6022 reduced the number of pathogenic effector CD4⁺ T cells (Th1 and Th17) in the spleen and decreased the expressions of proinflammatory cytokines associated with these T cells (IFN-γ and IL-17a), and increased the number of Treg cells with increased serum levels of IL-10. N6022 treatment also suppressed B cell maturation into plasma cells, lowering serum autoantibody levels against human MOG₁_-₁₂₅ IgG. Similar observations were made in the spinal cord, where N6022 treatment modulated B cell expression of regulatory versus effector cytokines (IL-10 > IL-6) and the expansion of regulatory versus effector T cells (Treg > Th1/Th17). These findings document that GSNOR inhibitors may potentially serve as effective immunomodulators in both T cell- and B cell-mediated EAE and multiple sclerosis.