Differential modulation of Ahr and Arid5a: A promising therapeutic strategy for autoimmune encephalomyelitis
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ABSTRACT: Graphical abstract 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 CD4+FoxP3+ T cells. Recent evidence indicates that AT-rich interactive domain-containing protein 5a (Arid5a) is required for EAE pathogenesis by stabilizing Il6 and OX40 mRNAs. However, the differential modulation of Ahr and Arid5a in autoimmunity as a therapeutic strategy is unexplored. Herein, an in silico, in vitro and in vivo 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 Il23a 3?UTR, a newly identified target mRNA. In EAE, Flavipin ameliorated disease severity, with reduced CD4+IL-17+ T cells, IL-6 and TNF-? and increased CD4+FoxP3+ T cells. Moreover, EAE amelioration was concomitant with reduced CD4+OX40+ and CD4+CD45+ 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.
SUBMITTER: Alzahrani A
PROVIDER: S-EPMC7783111 | biostudies-literature | 2020 Oct
REPOSITORIES: biostudies-literature
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