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Aryl Hydrocarbon Receptor Activation in Astrocytes by Laquinimod Ameliorates Autoimmune Inflammation in the CNS.

Authors :
Rothhammer V
Kenison JE
Li Z
Tjon E
Takenaka MC
Chao CC
Alves de Lima K
Borucki DM
Kaye J
Quintana FJ
Source :
Neurology(R) neuroimmunology & neuroinflammation [Neurol Neuroimmunol Neuroinflamm] 2021 Jan 06; Vol. 8 (2). Date of Electronic Publication: 2021 Jan 06 (Print Publication: 2021).
Publication Year :
2021

Abstract

Objective: MS is an autoimmune demyelinating disease of the CNS, which causes neurologic deficits in young adults and leads to progressive disability. The aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor, can drive anti-inflammatory functions in peripheral immune cells and also in CNS-resident cells. Laquinimod is a drug developed for the treatment of MS known to activate AHR, but the cellular targets of laquinimod are still not completely known. In this work, we analyzed the contribution of AHR activation in astrocytes to its beneficial effects in the experimental autoimmune encephalomyelitis (EAE) preclinical model of MS.<br />Methods: We used conditional knockout mice, in combination with genome-wide analysis of gene expression by RNA-seq and in vitro culture systems to investigate the effects of laquinimod on astrocytes.<br />Results: We found that AHR activation in astrocytes by laquinimod ameliorates EAE, a preclinical model of MS. Genome-wide RNA-seq transcriptional analyses detected anti-inflammatory effects of laquinimod in glial cells during EAE. Moreover, we established that the Delaq metabolite of laquinimod dampens proinflammatory mediator production while activating tissue-protective mechanisms in glia.<br />Conclusions: Taken together, these findings suggest that AHR activation by clinically relevant AHR agonists may represent a novel therapeutic approach for the treatment of MS.<br /> (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Details

Language :
English
ISSN :
2332-7812
Volume :
8
Issue :
2
Database :
MEDLINE
Journal :
Neurology(R) neuroimmunology & neuroinflammation
Publication Type :
Academic Journal
Accession number :
33408169
Full Text :
https://doi.org/10.1212/NXI.0000000000000946