Differential modulation of Ahr and Arid5a: A promising therapeutic strategy for autoimmune encephalomyelitis.

Multiple sclerosis (MS) is an autoimmune disease that involves demyelination of axons in the central nervous system (CNS) and affects patients worldwide. It has been demonstrated that ligand-activated aryl hydrocarbon receptor (Ahr) ameliorates experimental autoimmune encephalomyelitis (EAE), a murine model of MS, by increasing CD4FoxP3 T cells. Recent evidence indicates that AT-rich interactive domain-containing protein 5a (Arid5a) is required for EAE pathogenesis by stabilizing and mRNAs. However, the differential modulation of Ahr and Arid5a in autoimmunity as a therapeutic strategy is unexplored. Herein, an , and approach identified Flavipin (3,4,5-trihydroxy-6-methylphthalaldehyde) as an Ahr agonist that induces the expression of Ahr downstream genes in mouse CD4 T cells and CD11b macrophages. Interestingly, Flavipin inhibited the stabilizing function of Arid5a and its counteracting effects on Regnase-1 on the 3' untranslated region (3'UTR) of target mRNAs. Furthermore, it inhibited the stabilizing function of Arid5a on 3'UTR, a newly identified target mRNA. In EAE, Flavipin ameliorated disease severity, with reduced CD4IL-17 T cells, IL-6 and TNF-α and increased CD4FoxP3 T cells. Moreover, EAE amelioration was concomitant with reduced CD4OX40 and CD4CD45 T cells in the CNS. RNA interference showed that the modulatory effects of Flavipin on pro- and anti-inflammatory mediators in CD4 T cells and macrophages were Ahr- and/or Arid5a-dependent. In conclusion, our findings reveal differential modulation of Ahr and Arid5a as a new therapeutic strategy for MS.