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.
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.
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.
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.
Glossary
- AHR=
- aryl hydrocarbon receptor;
- EAE=
- experimental autoimmune encephalomyelitis;
- EDTA=
- ethylenediaminetetraacetic acid;
- GFAP=
- glial fibrillary acidic protein;
- GSEA=
- gene set enrichment analyses;
- IL=
- interleukin;
- IPA=
- ingenuity pathway analysis;
- Laq=
- laquinimod;
- NF-κB=
- nuclear factor kappa B;
- PPMS=
- primary progressive MS;
- qPCR=
- quantitative PCR;
- RRMS=
- relapsing-remitting MS;
- SPMS=
- secondary progressive MS;
- TNFα=
- tumor necrosis factor-α
Footnotes
Go to Neurology.org/NN for full disclosures. Funding information is provided at the end of the article.
The Article Processing Charge was funded by the NIH.
- Received June 12, 2020.
- Accepted in final form November 4, 2020.
- Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.
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