Related Experiment Video
Updated: May 6, 2026
Three-dimensional Confocal Analysis of Microglia/macrophage Markers of Polarization in Experimental Brain Injury
Published on: September 4, 2013
S100A9 deletion in microglia/macrophages ameliorates brain injury through the STAT6/PPARγ pathway in ischemic stroke
Xi Liu1, Junmin Wang2, Jian Jin3
1Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
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 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.
Conclusion:
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.
Insights
S100A9 in monocytes predicts ischemic stroke (IS) outcomes. Inhibiting S100A9 improves brain repair by modulating microglial and macrophage (M/M) responses via the STAT6/PPARγ pathway, offering a new therapeutic strategy for IS.
Area of Science:
- Neuroscience
- Immunology
- Pathology
Background:
- Microglia and macrophages (M/M) are key in brain repair post-ischemic stroke (IS).
- Modulating M/M phenotype is a therapeutic target for IS.
- S100A9's role in M/M and neuroinflammation requires elucidation.
Purpose of the Study:
- To investigate S100A9's role in M/M polarization and phagocytosis after IS.
- To explore the downstream STAT6/PPARγ signaling pathway.
- To assess S100A9 as a prognostic biomarker and therapeutic target for IS.
Main Methods:
- Clinical analysis of S100A9 in IS patients' monocytes.
- In vivo studies using S100A9 conditional knockout (CKO) mice and S100A9 inhibitor (PQD).
- Transcriptomics and in vitro assays to confirm the STAT6/PPARγ pathway involvement.
Main Results:
- S100A9 expression in classical monocytes correlates with poor IS prognosis.
- S100A9 CKO or PQD treatment reduced infarct volume, improved cerebral blood flow, and enhanced functional recovery.
- S100A9 inhibition promoted anti-inflammatory M/M phenotypes and efferocytosis, dependent on the STAT6/PPARγ pathway.
Conclusions:
- S100A9 serves as a potential prognostic biomarker for IS.
- S100A9 inhibition represents a novel therapeutic strategy for IS by modulating M/M polarization and phagocytosis.
- Targeting the S100A9/STAT6/PPARγ axis offers new drug development avenues for IS treatment.
