PMID- 33424253
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20210112
IS  - 1319-0164 (Print)
IS  - 2213-7475 (Electronic)
IS  - 1319-0164 (Linking)
VI  - 28
IP  - 12
DP  - 2020 Dec
TI  - Differential modulation of Ahr and Arid5a: A promising therapeutic strategy for 
      autoimmune encephalomyelitis.
PG  - 1605-1615
LID - 10.1016/j.jsps.2020.10.007 [doi]
AB  - 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-alpha 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.
CI  - (c) 2020 The Author(s).
FAU - Alzahrani, Abdullah
AU  - Alzahrani A
AD  - Biological Sciences Department, King Faisal University, Al-Ahsa, Hofouf, Saudi 
      Arabia.
FAU - Hanieh, Hamza
AU  - Hanieh H
AD  - Biological Sciences Department, King Faisal University, Al-Ahsa, Hofouf, Saudi 
      Arabia.
AD  - Department of Medical Analysis, Department of Biological Sciences, Al Hussein bin 
      Talal University, Ma'an, Jordan.
LA  - eng
PT  - Journal Article
DEP - 20201028
PL  - Saudi Arabia
TA  - Saudi Pharm J
JT  - Saudi pharmaceutical journal : SPJ : the official publication of the Saudi 
      Pharmaceutical Society
JID - 9705695
PMC - PMC7783111
OTO - NOTNLM
OT  - 3'UTR, 3' untranslated region
OT  - ActinD, actinomycin D
OT  - Ahr
OT  - Ahr, aryl hydrocarbon receptor
OT  - Arid5a
OT  - Arid5a, AT-rich interactive domain-containing protein 5a
OT  - Arnt, Ahr nuclear translocator
OT  - Autoimmunity
OT  - CFA, complete Freund's adjuvant
OT  - CNS, central nervous system
OT  - EAE, experimental autoimmune encephalomyelitis
OT  - Inflammation
OT  - LPS, lipopolysaccharide
OT  - MOG35-55, myelin oligodendrocyte glycoprotein
OT  - MS, multiple sclerosis
OT  - Multiple sclerosis
OT  - PAS-A and PAS-B, Per-Arnt-Sim domain
OT  - RBP, RNA-binding protein
OT  - RIP, RNA immunoprecipitation
OT  - SPF, specific pathogen-free
OT  - Therapeutic
OT  - miR, microRNA
COIS- 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.
EDAT- 2021/01/12 06:00
MHDA- 2021/01/12 06:01
PMCR- 2020/10/28
CRDT- 2021/01/11 05:35
PHST- 2020/08/09 00:00 [received]
PHST- 2020/10/18 00:00 [accepted]
PHST- 2021/01/11 05:35 [entrez]
PHST- 2021/01/12 06:00 [pubmed]
PHST- 2021/01/12 06:01 [medline]
PHST- 2020/10/28 00:00 [pmc-release]
AID - S1319-0164(20)30242-5 [pii]
AID - 10.1016/j.jsps.2020.10.007 [doi]
PST - ppublish
SO  - Saudi Pharm J. 2020 Dec;28(12):1605-1615. doi: 10.1016/j.jsps.2020.10.007. Epub 
      2020 Oct 28.