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

Autor:	Alzahrani A; Biological Sciences Department, King Faisal University, Al-Ahsa, Hofouf, Saudi Arabia., Hanieh H; Biological Sciences Department, King Faisal University, Al-Ahsa, Hofouf, Saudi Arabia.; Department of Medical Analysis, Department of Biological Sciences, Al Hussein bin Talal University, Ma'an, Jordan.
Jazyk:	angličtina
Zdroj:	Saudi pharmaceutical journal : SPJ : the official publication of the Saudi Pharmaceutical Society [Saudi Pharm J] 2020 Dec; Vol. 28 (12), pp. 1605-1615. Date of Electronic Publication: 2020 Oct 28.
DOI:	10.1016/j.jsps.2020.10.007
Abstrakt:	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-α 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. Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. (© 2020 The Author(s).)
Databáze:	MEDLINE
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