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

ABSTRACT: Microglia/macrophages (MM?) 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? polarization in intracerebral hemorrhage (ICH) is unknown. Herein, we comprehensively characterized MM? dynamics after ICH in mice and evaluated the relevance of MM? polarity to hematoma resolution. MM? 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 MM? classic activation dominated at the chronic stage of ICH. We enhanced MM? 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? 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? respond dynamically to brain hemorrhage by exhibiting diverse phenotypic changes at different stages of ICH. Alternative activation-skewed MM? aid in hematoma resolution, and IL-10 signaling might contribute to regulation of MM? phagocytosis and hematoma clearance in ICH.

SUBMITTER: Chang CF

PROVIDER: S-EPMC5540140 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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

Chang Che-Feng CF Wan Jieru J Li Qiang Q Renfroe Stephen C SC Heller Nicola M NM Wang Jian J

Neurobiology of disease 20170330

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 ...[more]

PMID: 28365213

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Project description:BackgroundEarly hematoma growth is associated with poor functional outcomes in patients with intracerebral hemorrhage (ICH). We aimed to explore whether quantitative hematoma heterogeneity in non-contrast computed tomography (NCCT) can predict early hematoma growth.MethodsWe used data from the Risk Stratification and Minimally Invasive Surgery in Acute Intracerebral Hemorrhage (Risa-MIS-ICH) trial. Our study included patients with ICH with a time to baseline NCCT <12 h and a follow-up CT duration <72 h. To get a Hounsfield unit histogram and the coefficient of variation (CV) of Hounsfield units (HUs), the hematoma was segmented by software using the auto-segmentation function. Quantitative hematoma heterogeneity is represented by the CV of hematoma HUs. Multivariate logistic regression was utilized to determine hematoma growth parameters. The discriminant score predictive value was assessed using the area under the ROC curve (AUC). The best cutoff was determined using ROC curves. Hematoma growth was defined as a follow-up CT hematoma volume increase of >6 mL or a hematoma volume increase of 33% compared with the baseline NCCT.ResultsA total of 158 patients were enrolled in the study, of which 31 (19.6%) had hematoma growth. The multivariate logistic regression analysis revealed that time to initial baseline CT (P = 0.040, odds ratio [OR]: 0.824, 95 % confidence interval [CI]: 0.686-0.991), "heterogeneous" in the density category (P = 0.027, odds ratio [OR]: 5.950, 95 % confidence interval [CI]: 1.228-28.828), and CV of hematoma HUs (P = 0.018, OR: 1.301, 95 % CI: 1.047-1.617) were independent predictors of hematoma growth. By evaluating the receiver operating characteristic curve, the CV of hematoma HUs (AUC = 0.750) has a superior predictive value for hematoma growth than for heterogeneous density (AUC = 0.638). The CV of hematoma HUs had an 18% cutoff, with a specificity of 81.9 % and a sensitivity of 58.1 %.ConclusionThe CV of hematoma HUs can serve as a quantitative hematoma heterogeneity index that predicts hematoma growth in patients with early ICH independently.

Dataset Information

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

Publications

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

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