Astrocyte KDM4A mediates chemokines and drives neutrophil infiltration to aggravate cerebral ischemia and reperfusion injury

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 Kdm4a knockout regulates neutrophil infiltration and alleviates brain injury following middle cerebral artery occlusion reperfusion. Furthermore, Kdm4a 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 Cxcl1 gene expression by demethylating histone H3 lysine 9 trimethylation at Cxcl1 gene promoters in astrocytes upon OGD/R injury. Our findings suggest that astrocyte KDM4A-mediated Cxcl1 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.