Differential effects of Flavipin on Ahr and Arid5a: A new therapeutic strategy for autoimmune encephalomyelitis

Abstract

Abstract Multiple sclerosis (MS) is a World-wide spread autoimmune disease that includes episode of demyelination in the central nervous system (CNS). Accumulating evidence has demonstrated that ligand-activated aryl hydrocarbon receptor (Ahr) improves pathological outcomes in experimental autoimmune encephalomyelitis (EAE), an experimental model of MS. Recent evidences have shown that AT-rich interactive domain-containing protein 5a (Arid5a), an RNA-binding protein, is required for development of EAE via stabilizing the mRNAs of interleukin-6 (Il6) and Ox40. To date, there are no reports studying both Ahr and Arid5a as a potential therapeutic strategy for MS. Thus, current work applied in silico, in vitro and in vivo approaches to identify a molecule that interacts with Ahr and Arid5a. The results identified Flavipin (3,4,5-trihydroxy-6-methylphthalaldehyde) as a new Ahr agonist that induces the expression of downstream genes in mice CD4+ T cells and CD11b+ macrophages. Interestingly, Flavipin inhibited the stabilizing function of Arid5a, and impaired its counteracting effects on RNase function of Regnase-1 on 3′ untranslated region (3′UTR) of Il6, Ox40 and signal transducer and activator of transcription 3 (stat3). In EAE, Flavipin ameliorated disease symptoms concomitant with inducing acetylcholinesterase (AChE)-targeting miR-132. It reduced the expression of Ox40 in CD4+ T cells and the number infiltrated CD4+CD45+ T cells in the CNS. Further analysis identified Il23a mRNA as a new target for Arid5a. Taken together, our findings provide first evidences on differential effects of Flavipin on Ahr and Arid5a and pave an avenue for a new therapeutic strategy for autoimmune diseases such as MS.