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

Che Feng Chang, Jieru Wan, Qiang Li, Stephen C. Renfroe, Nicola M. Heller, Jian Wang

Research output: Research - peer-reviewArticle

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 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 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.

LanguageEnglish (US)
Pages54-69
Number of pages16
JournalNeurobiology of Disease
Volume103
DOIs
StatePublished - Jul 1 2017

Fingerprint

Cerebral Hemorrhage
Microglia
Hematoma
Macrophages
Interleukin-10
Phenotype
rosiglitazone
Interleukin-10 Receptors
Intraventricular Injections
Intracranial Hemorrhages
Brain Diseases
Phagocytes
Neurologic Manifestations
Intraperitoneal Injections
Phagocytosis
Plastics
Monocytes
Cytokines
Wounds and Injuries
Brain

Keywords

  • Hematoma resolution
  • Interleukin-10
  • Intracerebral hemorrhage
  • Microglia/macrophage polarization
  • Phagocytosis

ASJC Scopus subject areas

  • Neurology

Cite this

Alternative activation-skewed microglia/macrophages promote hematoma resolution in experimental intracerebral hemorrhage. / Chang, Che Feng; Wan, Jieru; Li, Qiang; Renfroe, Stephen C.; Heller, Nicola M.; Wang, Jian.

In: Neurobiology of Disease, Vol. 103, 01.07.2017, p. 54-69.

Research output: Research - peer-reviewArticle

Chang, Che Feng ; Wan, Jieru ; Li, Qiang ; Renfroe, Stephen C. ; Heller, Nicola M. ; Wang, Jian. / Alternative activation-skewed microglia/macrophages promote hematoma resolution in experimental intracerebral hemorrhage. In: Neurobiology of Disease. 2017 ; Vol. 103. pp. 54-69
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