The potential role of S-nitrosoglutathione reductase in astrocyte BAFF expression and B cell activation in experimental autoimmune encephalomyelitis.

B cell-activating factor (BAFF) is a key mediator of B cell-driven autoimmune pathology. In mice with experimental autoimmune encephalomyelitis (EAE), a widely used model of multiple sclerosis (MS), we observed a pronounced accumulation of B cells within the spinal cord, alongside elevated BAFF expression, particularly in GFAP+ activated astrocytes located in the subpial-region. This upregulation of BAFF coincided with the infiltration of CD4+ T cells, notably Th1 cells producing IFNγ, a cytokine critical for inducing BAFF gene expression in astrocytes. Concurrently, elevated BAFF levels in the spinal cords of EAE mice were associated with increased expression of S-nitrosoglutathione (GSNO) reductase (GSNOR), the enzyme that degrades GSNO, a molecule known for its anti-inflammatory properties. Pharmacological inhibition of GSNOR using N6022, a reversible inhibitor, significantly reduced BAFF expression and decreased B cell accumulation in the CNS. In vitro, both GSNO and N6022 suppressed IFNγ- and TNFα-induced BAFF expression in cultured astrocytes by inhibiting STAT1 and NF-κB activation. Furthermore, co-culture of B cells with IFNγ/TNFα-stimulated astrocytes, or exposure to their conditioned media, resulted in an increased number of B cells and enhanced IL-6 production. These effects were attenuated either by pretreating astrocytes with GSNO or by applying BAFF-neutralizing antibodies to B cells. Collectively, these findings suggest that GSNOR modulates astrocytic BAFF expression, thereby influencing B cell activation and their IL-6-mediated functions in EAE. Modulation of this pathway may represent a promising avenue for future investigation into immune regulation in MS and related autoimmune conditions.