S100A9 deletion in microglia/macrophages ameliorates brain injury through the STAT6 / PPARγ pathway in ischemic stroke

作者：Xi Liu, Junmin Wang, Junmin Wang, Jian Jin, Qiongqiong Hu, Ting Zhao, Jian Wang, Jian Wang, Jianbo Gao, Man Jiang · 发表于：CNS Neuroscience & Therapeutics · 年份：2024 · DOI：10.1111/cns.14881 · 被引用次数：28 · 研究领域：S100 Proteins and Annexins、Neuroinflammation and Neurodegeneration Mechanisms、Intracerebral and Subarachnoid Hemorrhage Research

BACKGROUND: Microglia and infiltrated macrophages (M/M) are integral components of the innate immune system that play a critical role in facilitating brain repair after ischemic stroke (IS) by clearing cell debris. Novel therapeutic strategies for IS therapy involve modulating M/M phenotype shifting. This study aims to elucidate the pivotal role of S100A9 in M/M and its downstream STAT6/PPARγ signaling pathway in neuroinflammation and phagocytosis after IS. METHODS: In the clinical study, we initially detected the expression pattern of S100A9 in monocytes from patients with acute IS and investigated its association with the long-term prognosis. In the in vivo study, we generated the S100A9 conditional knockout (CKO) mice and compared the stroke outcomes with the control group. We further tested the S100A9-specific inhibitor paqunimod (PQD), for its pharmaceutical effects on stroke outcomes. Transcriptomics and in vitro studies were adopted to explore the mechanism of S100A9 in modulating the M/M phenotype, which involves the regulation of the STAT6/PPARγ signaling pathway. RESULTS: S100A9 was predominantly expressed in classical monocytes and was correlated with unfavorable outcomes in patients of IS. S100A9 CKO mitigated infarction volume and white matter injury, enhanced cerebral blood flow and functional recovery, and prompted anti-inflammation phenotype and efferocytosis after tMCAO. The STAT6/PPARγ pathway, an essential signaling cascade involved in immune response and i...