Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
Department of Human Anatomy, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China.
CNS Neurosci Ther. 2024 Aug;30(8):e14881. doi: 10.1111/cns.14881.
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.
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.
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 inflammation, might be the downstream target mediated by S100A9 deletion, as evidenced by the STAT6 phosphorylation inhibitor AS1517499 abolishing the beneficial effect of S100A9 inhibition in tMCAO mice and cell lines. Moreover, S100A9 inhibition by PQD treatment protected against neuronal death in vitro and brain injuries in vivo.
This study provides evidence for the first time that S100A9 in classical monocytes could potentially be a biomarker for predicting IS prognosis and reveals a novel therapeutic strategy for IS. By demonstrating that S100A9-mediated M/M polarization and phagocytosis can be reversed by S100A9 inhibition in a STAT6/PPARγ pathway-dependent manner, this study opens up new avenues for drug development in the field.
小胶质细胞和浸润的巨噬细胞（M/M）是先天免疫系统的组成部分，在通过清除细胞碎片促进缺血性中风（IS）后的大脑修复方面发挥着关键作用。用于 IS 治疗的新型治疗策略涉及调节 M/M 表型转变。本研究旨在阐明 S100A9 在 M/M 中的关键作用及其下游 STAT6/PPARγ 信号通路在 IS 后的神经炎症和吞噬作用中的作用。
在临床研究中，我们最初检测了急性 IS 患者单核细胞中 S100A9 的表达模式，并研究了其与长期预后的关系。在体内研究中，我们生成了 S100A9 条件敲除（CKO）小鼠，并将其与对照组进行了比较。我们进一步测试了 S100A9 特异性抑制剂 paqunimod（PQD）对中风结果的药物作用。采用转录组学和体外研究来探讨 S100A9 调节 M/M 表型的机制，该机制涉及 STAT6/PPARγ 信号通路的调节。
S100A9 主要在经典单核细胞中表达，与 IS 患者的不良结局相关。S100A9 CKO 减轻了梗死体积和白质损伤，增强了脑血流和功能恢复，并促进了 tMCAO 后的抗炎表型和吞噬作用。STAT6/PPARγ 通路是参与免疫反应和炎症的重要信号级联，可能是 S100A9 缺失介导的下游靶标，因为 STAT6 磷酸化抑制剂 AS1517499 消除了 S100A9 抑制在 tMCAO 小鼠和细胞系中的有益作用。此外，PQD 处理通过抑制 S100A9 来保护体外神经元死亡和体内脑损伤。
本研究首次提供证据表明，经典单核细胞中的 S100A9 可能成为预测 IS 预后的生物标志物，并揭示了一种用于 IS 的新治疗策略。通过证明 S100A9 介导的 M/M 极化和吞噬作用可以通过 S100A9 抑制以 STAT6/PPARγ 通路依赖的方式逆转，这为该领域的药物开发开辟了新途径。
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