Autism-associated CHD8 controls reactive gliosis and neuroinflammation via remodeling chromatin in astrocytes.

Reactive changes of glial cells during neuroinflammation impact brain disorders and disease progression. Elucidating the mechanisms that control reactive gliosis may help us to understand brain pathophysiology and improve outcomes. Here, we report that adult ablation of autism spectrum disorder (ASD)-associated CHD8 in astrocytes attenuates reactive gliosis via remodeling chromatin accessibility, changing gene expression. Conditional Chd8 deletion in astrocytes, but not microglia, suppresses reactive gliosis by impeding astrocyte proliferation and morphological elaboration. Astrocyte Chd8 ablation alleviates lipopolysaccharide-induced neuroinflammation and septic-associated hypothermia in mice. Astrocytic CHD8 plays an important role in neuroinflammation by altering the chromatin landscape, regulating metabolic and lipid-associated pathways, and astrocyte-microglia crosstalk. Moreover, we show that reactive gliosis can be directly mitigated in vivo using an adeno-associated virus (AAV)-mediated Chd8 gene editing strategy. These findings uncover a role of ASD-associated CHD8 in the adult brain, which may warrant future exploration of targeting chromatin remodelers in reactive gliosis and neuroinflammation in injury and neurological diseases.
Competing Interests: Declaration of interests T.I. is a co-founder, member of the advisory board, and has an equity interest in Data4Cure and Serinus Biosciences. He is a consultant for and has an equity interest in Ideaya BioSciences and Light Horse Therapeutics. The terms of these arrangements have been reviewed and approved by University of California, San Diego in accordance with its conflict of interest policies. N.E.S. is an adviser to Qiagen and a co-founder of and adviser to TruEdit Bio and OverT Bio.
(Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)