Journal Article Research Support, Non-U.S. Gov't Ppublish 7 citations
PubMed: 38008899 DOI: 10.1177/0271678X231216158
Astrocyte KDM4A mediates chemokines and drives neutrophil infiltration to aggravate cerebral ischemia and reperfusion injury.
J Cereb Blood Flow Metab 44(4):491-507
Authors: Jing Huang, Xin-Shang Wang, Tian Gao, Xing Wang, Man-Yang Yu, Hao-Xin Song, Bi-Yan Wang, Ling-Mei Li, Qiang Zeng, Hui-Nan Zhang
Affiliations
- Department of Health Management, Second Affiliated Hospital, Fourth Military Medical University, Xi'an, China.
- Department of Neurology, Second Affiliated Hospital, Fourth Military Medical University, Xi'an, China.
- Health Management Institute, Second Medical Center & National Clinical Research Center for Geriatric Diseases, Chinese People's Liberation Army General Hospital, Beijing, China.
- Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an, China.
- Department of Health Management, Second Affiliated Hospital, Fourth Military Medical University, Xi'an, China. Department of Neurology, Second Affiliated Hospital, Fourth Military Medical University, Xi'an, China.
Abstract
Neutrophils plays a crucial role in acute ischemic brain injury and have emerged as potential treatment targets to mitigate such injuries. Lysine-specific demethylase 4 A (KDM4A), a member of the histone lysine demethylase family of enzymes involved in transcriptional regulation of gene expression, is upregulated during hypoxic events. However, the exact role of KDM4A in the pathological process of ischemic stroke remains largely unexplored. Our findings reveal that there was an upregulation of KDM4A levels in reactive astrocytes within both stroke mouse models and in vitro oxygen-glucose deprivation/regeneration (OGD/R) models. Using a conditional knockout mouse, we observed that astrocytic knockout regulates neutrophil infiltration and alleviates brain injury following middle cerebral artery occlusion reperfusion. Furthermore, deficiency astrocytes displayed lower chemokine C-X-C motif ligand 1 (CXCL1) level upon OGD/R and decreased neutrophil infiltration in a transwell system. Mechanistically, KDM4A, in cooperation with nuclear factor-kappa B (NF-κB), activates gene expression by demethylating histone H3 lysine 9 trimethylation at gene promoters in astrocytes upon OGD/R injury. Our findings suggest that astrocyte KDM4A-mediated activation contributes to neutrophil infiltration via cooperation with NF-κB, and KDM4A in astrocytes may serve as a potential therapeutic target to modulate neutrophil infiltration after stroke.
MeSH
Neutrophil Infiltration, Genes, Brain Injuries, Astrocytes, Chemokines, Stroke, Brain, Neutrophils, Reperfusion, Histones, Reperfusion Injury, Therapeutics, Ischemia, Lysine, Gene Expression