Iguratimod Ameliorates the Severity of Secondary Progressive Multiple Sclerosis in Model Mice by Directly Inhibiting IL-6 Production and Th17 Cell Migration via Mitigation of Glial Inflammation

SIMPLE SUMMARY: We previously developed a novel model of progressive multiple sclerosis, called progressive experimental autoimmune encephalomyelitis, in mice with oligodendroglia-specific knockout of the connexin-47 gene. Our previous research showed that iguratimod, an antirheumatic drug, effectively ameliorated acute experimental autoimmune encephalomyelitis. In this study, iguratimod was administered to mice with progressive experimental autoimmune encephalomyelitis, which resulted in improvement of clinical severity, reduced demyelination, and decreased glial inflammation. Interleukin-6 levels and T helper 17 cell infiltration were also reduced. Furthermore, T helper 17 cell migration and interleukin-6 production in cell culture were inhibited by iguratimod. In conclusion, iguratimod successfully mitigated clinical signs of progressive experimental autoimmune encephalomyelitis by suppressing T helper 17 migration and inhibiting interleukin-6 production in proinflammatory-activated glial cells. ABSTRACT: We previously reported a novel secondary progressive multiple sclerosis (SPMS) model, progressive experimental autoimmune encephalomyelitis (pEAE), in oligodendroglia-specific Cx47-inducible conditional knockout (Cx47 icKO) mice. Based on our prior study showing the efficacy of iguratimod (IGU), an antirheumatic drug, for acute EAE treatment, we aimed to elucidate the effect of IGU on the SPMS animal model. We induced pEAE by immunizing Cx47 icKO mice with myelin oligodendrocyte glycoprotein peptide 35–55. IGU was orally administered from 17 to 50 days post-immunization. We also prepared a primary mixed glial cell culture and measured cytokine levels in the culture supernatant after stimulation with designated cytokines (IL-1α, C1q, TNF-α) and lipopolysaccharide. A migration assay was performed to evaluate the effect of IGU on the migration ability of T cells toward mixed glial cell cultures. IGU treatment ameliorated the clinical signs of pEAE, decreased the demyelinated area, and attenuated glial inflammation on immunohistochemical analysis. Additionally, IGU decreased the intrathecal IL-6 level and infiltrating Th17 cells. The migration assay revealed reduced Th17 cell migration and IL-6 levels in the culture supernatant after IGU treatment. Collectively, IGU successfully mitigated the clinical signs of pEAE by suppressing Th17 migration through inhibition of IL-6 production by proinflammatory-activated glial cells.