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Macrophage Nuclear Receptor Corepressor 1 Deficiency Protects Against Ischemic Stroke in Mice
Shuai Shao1, Yan-Lin Chen1, Lin-Juan Du2,3
1Department of Neurosurgery, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Abstract:
Microglia/macrophage activation plays an essential role in Ischemic stroke (IS). Nuclear receptor corepressor 1 (NCoR1) has been identified as a vital regulator in macrophages. The present study aims to explore the functions of macrophage NCoR1 in IS. Macrophage NCoR1 knockout (MNKO) mice and littermate control mice were subjected to middle cerebral artery occlusion (MCAO). Our data showed that macrophage NCoR1 deficiency significantly reduced the infarct size and infarct volume as well as brain edema after MCAO. Additionally, MNKO induced less microglia/macrophage infiltration and activation, neuroinflammation, apoptosis of neuronal cells, and BBB disruption in brains after IS. Mechanistic studies revealed that NCoR1 interacted with LXRβ in microglia and MNKO impaired the activation of the Nuclear factor-κB signaling pathway in brains after IS. Our data demonstrated that macrophage NCoR1 deficiency inhibited microglia/macrophage activation and protected against IS. Targeting NCoR1 in microglia/macrophage may be a potential approach for IS treatment.
Insights
Targeting Nuclear receptor corepressor 1 (NCoR1) in macrophages reduces brain damage after ischemic stroke (IS). Deleting NCoR1 in these cells protected against stroke by reducing inflammation and cell death.
Area of Science:
- Neuroscience
- Immunology
- Molecular Biology
Background:
- Microglia and macrophage activation are critical in ischemic stroke (IS) pathogenesis.
- Nuclear receptor corepressor 1 (NCoR1) is a key regulator in macrophage function.
Purpose of the Study:
- To investigate the role of macrophage NCoR1 in the context of ischemic stroke.
- To determine if NCoR1 deficiency in macrophages offers protection against stroke-induced brain injury.
Main Methods:
- Middle cerebral artery occlusion (MCAO) model in mice with macrophage-specific NCoR1 knockout (MNKO).
- Assessment of infarct size, brain edema, immune cell infiltration, neuroinflammation, neuronal apoptosis, and blood-brain barrier (BBB) integrity.
- Exploration of molecular mechanisms involving NCoR1, LXRβ, and nuclear factor-κB (NF-κB) signaling.
Main Results:
- Macrophage NCoR1 deficiency significantly reduced infarct size, volume, and brain edema post-MCAO.
- MNKO mice exhibited decreased microglia/macrophage infiltration and activation, reduced neuroinflammation, less neuronal apoptosis, and preserved BBB integrity.
- NCoR1 was found to interact with LXRβ in microglia, and its absence impaired NF-κB pathway activation.
Conclusions:
- Macrophage NCoR1 deficiency confers protection against ischemic stroke.
- Targeting NCoR1 in microglia/macrophages presents a potential therapeutic strategy for treating ischemic stroke.
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