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Three-dimensional Confocal Analysis of Microglia/macrophage Markers of Polarization in Experimental Brain Injury
Published on: September 4, 2013
Alternative activation-skewed microglia/macrophages promote hematoma resolution in experimental intracerebral
Che-Feng Chang1, Jieru Wan2, Qiang Li2
1Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, United States; Department of Neurology, Yale University School of Medicine, New Haven, CT 06511, United States.
Abstract:
Microglia/macrophages (MMΦ) are highly plastic phagocytes that can promote both injury and repair in diseased brain through the distinct function of classically activated and alternatively activated subsets. The role of MMΦ polarization in intracerebral hemorrhage (ICH) is unknown. Herein, we comprehensively characterized MMΦ dynamics after ICH in mice and evaluated the relevance of MMΦ polarity to hematoma resolution. MMΦ accumulated within the hematoma territory until at least 14days after ICH induction. Microglia rapidly reacted to the hemorrhagic insult as early as 1-1.5h after ICH and specifically presented a "protective" alternatively activated phenotype. Substantial numbers of activated microglia and newly recruited monocytes also assumed an early alternatively activated phenotype, but the phenotype gradually shifted to a mixed spectrum over time. Ultimately, markers of MMΦ classic activation dominated at the chronic stage of ICH. We enhanced MMΦ alternative activation by administering intraperitoneal injections of rosiglitazone, and subsequently observed elevations in CD206 expression on brain-isolated CD11b+ cells and increases in IL-10 levels in serum and perihematomal tissue. Enhancement of MMΦ alternative activation correlated with hematoma volume reduction and improvement in neurologic deficits. Intraventricular injection of alternative activation signature cytokine IL-10 accelerated hematoma resolution, whereas microglial phagocytic ability was abolished by IL-10 receptor neutralization. Our results suggest that MMΦ respond dynamically to brain hemorrhage by exhibiting diverse phenotypic changes at different stages of ICH. Alternative activation-skewed MMΦ aid in hematoma resolution, and IL-10 signaling might contribute to regulation of MMΦ phagocytosis and hematoma clearance in ICH.
Insights
Microglia/macrophages (MMΦ) polarization impacts brain injury. In intracerebral hemorrhage (ICH), alternatively activated MMΦ promote hematoma resolution, suggesting therapeutic potential.
Area of Science:
- Neuroscience
- Immunology
- Pathology
Background:
- Microglia/macrophages (MMΦ) are crucial immune cells in the brain, exhibiting plasticity that influences disease outcomes.
- MMΦ polarization into classically (M1) and alternatively (M2) activated states dictates their role in injury and repair.
- The specific role of MMΦ polarization in intracerebral hemorrhage (ICH) remains largely unexplored.
Purpose of the Study:
- To comprehensively characterize MMΦ dynamics and polarization following ICH in a mouse model.
- To investigate the functional relevance of MMΦ polarity in hematoma resolution and neurological recovery.
- To explore therapeutic strategies targeting MMΦ polarization for improved ICH outcomes.
Main Methods:
- Induction of ICH in mice and subsequent analysis of MMΦ accumulation and phenotype.
- Flow cytometry and immunohistochemistry to identify and quantify MMΦ subsets (e.g., CD11b+, CD206+).
- Pharmacological manipulation (rosiglitazone) to enhance alternative MMΦ activation and cytokine administration (IL-10).
Main Results:
- MMΦ rapidly infiltrate the hematoma site post-ICH, initially displaying an alternatively activated phenotype that shifts over time.
- Enhancing alternative MMΦ activation with rosiglitazone correlated with reduced hematoma volume and improved neurological function.
- IL-10 administration accelerated hematoma resolution, while IL-10 receptor blockade impaired microglial phagocytosis.
Conclusions:
- MMΦ exhibit dynamic phenotypic changes throughout the different stages of ICH.
- Promoting an alternatively activated MMΦ phenotype aids in hematoma resolution and functional recovery.
- IL-10 signaling plays a significant role in regulating MMΦ phagocytosis and clearance of blood products in ICH.
