Alternative activation-skewed microglia/macrophages promote hematoma resolution in experimental intracerebral hemorrhage

Microglia/macrophages (MM Phi) 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 MM Phi polarization in intracerebral hemorrhage (ICH) is unknown. Herein, we comprehensively characterized MM Phi dynamics after ICH in mice and evaluated the relevance of MM Phi polarity to hematoma resolution. MM Phi accumulated within the hematoma territory until at least 14 days after ICH induction. Microglia rapidly reacted to the hemorrhagic insult as early as 1-1.5 h 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 MM Phi classic activation dominated at the chronic stage of ICH. We enhanced MM Phi 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 MM Phi 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 MM Phi respond dynamically to brain hemorrhage by exhibiting diverse phenotypic changes at different stages of ICH. Alternative activation-skewed MM Phi aid in hematoma resolution, and IL-10 signaling might contribute to regulation of MM Phi phagocytosis and hematoma clearance in ICH. (C) 2017 Elsevier Inc. All rights reserved.