ArticleCNS neuroscience & therapeutics2024
S100A9 deletion in microglia/macrophages ameliorates brain injury through the STAT6/PPARγ pathway in ischemic stroke.
Article in CNS neuroscience & therapeutics, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed.
- Lung microbiota-derived deoxyinosine alleviates TBI-aggravated sepsis-induced lung injury via the S100A9/RAGE pathway.Journal of neuroinflammation · 2026Article
- Schizophrenia as a Disorder of Biological Barriers: A Narrative Review and Potential Interventions.International journal of molecular sciences · 2026Review
- Mitochondrial Transplantation Therapy for Ischemic Stroke: Progress and Challenges.Cellular and molecular neurobiology · 2026Review
- Autophagy activation by the Becn1Brain, behavior, and immunity · 2026Article
- Microglial PD-1/PD-L1 axis in CNS demyelinating diseases: a dual immunoregulatory perspective.Frontiers in cellular neuroscience · 2026Review
- SLC25A1-Mediated Cholesterol Accumulation Promotes Endometriosis Progression by Enhancing Endometrial Stromal Cell Proliferation, Invasion, and M2 Macrophage Polarization.International journal of biological sciences · 2026Article
- PPAR-γ Inhibits Chronic Apical Periodontitis by Facilitating Macrophage Efferocytosis.International journal of molecular sciences · 2025Article
- Neutrophil Mobilization Triggers Microglial Functional Change to Exacerbate Cerebral Ischemia-Reperfusion Injury.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- The role of efferocytosis in ischemic stroke and insights from retinopathy.Trends in neurosciences · 2025Review
- Microglia efferocytosis: an emerging mechanism for the resolution of neuroinflammation in Alzheimer's disease.Journal of neuroinflammation · 2025Review
- Krüppel-like factor 4 control of immune cell function.Frontiers in immunology · 2025Review
- Microglial pyroptosis as a therapeutic target after traumatic spinal cord injury: current progress and future directions.Frontiers in immunology · 2025Review
- Correlation of serum calprotectin with outcome of acute cerebral infarction.Open medicine (Warsaw, Poland) · 2025Article
- Targeting microglia polarization with Chinese herb-derived natural compounds for neuroprotection in ischemic stroke.Frontiers in cell and developmental biology · 2025Review
- Article
- Myeloid-specific S100A8/A9 deficiency attenuates atrial fibrillation through prevention of TLR4/NF-kB-mediated immune cell recruitment and inflammation.Frontiers in immunology · 2025Article
- Is postoperative cognitive dysfunction a disease of microglial inflammatory memory? A state-transition model from metabolic stress to epigenetic lock-in.Frontiers in molecular neuroscience · 2025Review
- S100A9 deletion in microglia/macrophages ameliorates brain injury through the STAT6/PPARγ pathway in ischemic stroke.CNS neuroscience & therapeutics · 2024Article
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8 authors.
Funding
Abstract
backgroundMicroglia 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.
methodsIn 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.
resultsS100A9 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.
conclusionThis 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.
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