Single-cell RNA sequencing reveals S100A8/A9hi neutrophils-induced endothelial cell death and lymphocyte infiltration after ischemic stroke

Song Wang; Yutao Wang; Sichen Wang; Yuhan Sun; Yitong Du; Song Zhang; Jingyi Yao; Jiangxu Wu; Dan Xie

doi:10.1016/j.bbrc.2024.151023

Single-cell RNA sequencing reveals S100A8/A9^hi neutrophils-induced endothelial cell death and lymphocyte infiltration after ischemic stroke

Biochem Biophys Res Commun. 2024 Nov 19:741:151023. doi: 10.1016/j.bbrc.2024.151023. Online ahead of print.

Authors

Song Wang¹, Yutao Wang², Sichen Wang³, Yuhan Sun³, Yitong Du³, Song Zhang¹, Jingyi Yao¹, Jiangxu Wu¹, Dan Xie⁴

Affiliations

¹ Experimental and Translational Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China.
² Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China; State Key Laboratory of Digestive Health, National Clinical Research Center for Digestive Diseases, Beijing, 100050, China.
³ Department of Neurology, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China.
⁴ Department of Neurology, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China. Electronic address: danxiedx@126.com.

PMID: 39579533
DOI: 10.1016/j.bbrc.2024.151023

Abstract

Stroke is a major global cause of death and disability, with ischemic stroke being the most common type. The disruption of the blood-brain barrier (BBB) is a key factor in the pathophysiology of ischemic stroke, allowing immune cells to infiltrate and worsening neuroinflammation. This study uses single-cell RNA sequencing (scRNA-seq) to examine the transcriptional changes in neutrophils, endothelial cells, and T cells during ischemic stroke. Our findings indicate a significant increase in neutrophil and lymphocyte infiltration, along with a notable decrease in endothelial cell populations, demonstrating severe BBB disruption. Differential gene expression analysis shows that endothelial cells lose important characteristics post-stroke, while lymphocytes activate cytotoxic pathways that may lead to neuronal damage. Additionally, we reveal the contrasting roles of CXCR2 and CXCR4 in neutrophil movement and identify neutrophil-derived damage-associated molecular patterns (DAMPs) and matrix metalloproteinases (MMPs) as key drivers of endothelial cell apoptosis. Notably, the S100A8/A9 inhibitor paquinimod significantly protects neurons and reduces lymphocyte infiltration, suggesting that targeting S100A8/A9 could be a promising therapeutic strategy for reducing neurological deficits after ischemic stroke. Overall, these results enhance our understanding of the complex interactions between immune cells and the BBB in ischemic stroke, paving the way for innovative therapeutic approaches aimed at maintaining brain integrity and improving patient outcomes.

Keywords: Ischemic stroke; Lymphocyte; S100A8/A9; Single-cell RNA-Sequencing.