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

Abstract

ObjectiveMS 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.MethodsWe 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.ResultsWe 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.ConclusionsTaken together, these findings suggest that AHR activation by clinically relevant AHR agonists may represent a novel therapeutic approach for the treatment of MS.

Astrocyte-Derived Pleiotrophin Mitigates Late-Stage Autoimmune CNS Inflammation

“…This was further recapitulated in the recent CONCERTO trial, in which oral Laq treatment led to a significant reduction in brain volume loss compared to the placebo group, as well as a numerical reduction in time to first relapse and annualized relapse rate as exploratory endpoints, while it did not alter 3-month confirmed disability progression ( 43 ). Together with observations of protective astrocyte signaling following oral administration of Laq during EAE ( 28 ), one may speculate that this positive effect of Laq on GM loss may, at least to some extent, be carried by increased levels of PTN, which limits inflammatory signaling in glial cells and supports neuronal survival, as we have demonstrated in vitro and in vivo . However, a detailed examination of brain tissue obtained from Laq-treated MS patients would be needed to confirm this hypothesis.…”

The cyclin‐dependent kinase inhibitor p27Kip1 interacts with the aryl hydrocarbon receptor and negatively regulates its transcriptional activity

“…A long list of synthetic [1,[7][8][9][10][11][12][13], endogenous [14,15] and dietary molecules [16] have been identified that bind to AhR, in addition to ligands produced by commensal microbiota [17]. There is significant interest in developing AhR-targeted therapeutics for multiple diseases, particularly autoimmune disorders [18][19][20] and cancer [3,[8][9][10]21,22]. The feasibility of therapeutically targeting AhR is supported by the absence of overt toxicity in vivo when select highaffinity ligands are administered [11,19,20].…”

Astrocytes and Inflammatory T Helper Cells: A Dangerous Liaison in Multiple Sclerosis

“…Treatment of human astrocytes with LQ inhibited IL-1β-induced downregulation of glutamate transporters GLAST and GLT1 and restored astrocyte glutamate uptake ( 178 ). Consistently, LQ treatment ameliorated EAE by suppressing, in astrocytes, the expression of inflammatory mediators such as IL-6 and ROS and by inducing a transcriptional program associated to homeostatic chemokines, neurotrophin, axonal guidance and transendothelial migration ( 182 ).…”