Microglia/Macrophage Polarization After Experimental Intracerebral Hemorrhage

Zhao, Hao; Garton, Thomas; Keep, Richard F.; Hua, Ya; Xi, Guohua

doi:10.1007/s12975-015-0428-4

Cited by 90 publications

(68 citation statements)

References 34 publications

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“…Recent research has studied microglia/macrophage activation and polarization in several neurological conditions, including brain ischemia [10, 11, 16–18]. However, the polarized microglia/macrophage activation after ICH has not been well studied [36, 37]. The present study reveals the time course of polarized microglia/macrophage activation after ICH, which should provide a solid basis for further investigation to microglia/macrophage-mediated inflammatory injury and repair after ICH.…”

Section: Discussionmentioning

confidence: 59%

Microglia Activation and Polarization After Intracerebral Hemorrhage in Mice: the Role of Protease-Activated Receptor-1

Wan

Cheng

Jin

et al. 2016

Transl. Stroke Res.

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122

103

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Polarized microglia play a dual (beneficial/detrimental) role in neurological diseases. However, the status and the factors that modulate microglia polarization in intracerebral hemorrhage (ICH) remain unclear. In the present study, we investigated the role of protease-activated receptor-1 (PAR-1, a thrombin receptor) in ICH-induced microglia polarization in mice. Male wild-type (WT) and PAR-1 knockout (PAR-1 KO) mice received an infusion of 30-μL autologous blood or saline into the right basal ganglia. Mice were euthanized at different time points and the brains were used for Western blotting and immunohistochemistry. Some mice had magnetic resonance imaging. We found that ICH induced microglia activation and polarization. M1 phenotypic markers were markedly increased and reached a peak as early as 4 h, remained high at 3 days and decreased 7 days after ICH. M2 phenotypic markers were upregulated later than M1 markers reaching a peak at day 1 and declining by day 7 after ICH. PAR-1 was upregulated after ICH and expressed in the neurons and microglia. ICH induced less brain swelling and neuronal death in PAR-1 KO mice, and this was associated with less M1 polarization and reduced proinflammatory cytokine levels in the brain. In conclusion, these results suggest that polarized microglia occur dynamically after ICH and that PAR-1 plays a role in the microglia activation and polarization.

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Section: Discussionmentioning

confidence: 59%

Microglia Activation and Polarization After Intracerebral Hemorrhage in Mice: the Role of Protease-Activated Receptor-1

Wan

Cheng

Jin

et al. 2016

Transl. Stroke Res.

Self Cite

122

103

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“…Accumulating evidence indicates that classically activated and alternatively activated MMΦ within the lesion area can individually contribute to tissue damage or repair in the brain under conditions of spinal cord injury (Kigerl et al, 2009; Kroner et al, 2014), traumatic brain injury (Kumar et al, 2013; Wang et al, 2013), ischemic stroke (Hu et al, 2012), multiple sclerosis (Mikita et al, 2011), and Parkinson’s disease (Pisanu et al, 2014). To date, no study has comprehensively characterized MMΦ dynamics or delineated the functional significance of MMΦ phenotype on hematoma resolution in vivo (Wan et al, 2016; Zhang et al, 2016; Zhao et al, 2015a). …”

Section: Introductionmentioning

confidence: 99%

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

Chang

Wan

et al. 2017

Neurobiology of Disease

109

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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.

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“…Additionally, iron plays an important role in brain injury after experimental intracerebral hemorrhage (ICH) (18-20), intraventricular hemorrhage (IVH) (21, 22) and SAH (23). Our previous studies indicated that iron levels in CSF increase almost 14-fold after ICH on the third day, and remain high for at least one month after experimental ICH.…”

Section: Introductionmentioning

confidence: 99%

MRI Characterization in the Acute Phase of Experimental Subarachnoid Hemorrhage

Guo

Wilkinson

Thompson

et al. 2016

Transl. Stroke Res.

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A number of mechanisms have been proposed for the early brain injury after subarachnoid hemorrhage (SAH). In this study, we investigated the radiographic characteristics and influence of gender on early brain injury after experimental SAH. SAH was induced by endovascular perforation in male and female rats. Magnetic resonance imaging was performed in a 7.0-T Varian MR scanner at 24 hours after SAH. The occurrence and size of T2 lesions, ventricular dilation and white matter injury (WMI) was determined on T2 weighted images (T2WI). The effects of SAH on heme oxygenase-1 and fibrin/fibrinogen were examined by Western blotting and immunohistochemistry. SAH severity was assessed using a MRI grading system and neurological function was evaluated according to a modified Garcia’s scoring system. T2-hyperintensity areas and enlarged ventricles were observed in T2WI coronal sections 24 hours after SAH. The overall incidence of T2-lesions, WMI and hydrocephalus was 54, 20 and 63%, respectively. Female rats had a higher incidence of T2-hyperintensity lesions and hydrocephalus, as well as larger T2 lesion volumes and higher average ventricular volume. SAH rats graded at 3-4 (our previously validated MRI grading scale) had larger T2 lesion volumes, more hydrocephalus and worse neurological function compared with those graded at 0-2. In conclusion, T2-lesion, WMI and hydrocephalus were the most prevalent MRI characteristics 24 hours after experimental SAH. The T2-lesion area matched with fibrinogen/fibrin positive staining in the acute phase of SAH. SAH induced more severe brain injury in females compared to males in the acute phase of SAH.

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Microglia/Macrophage Polarization After Experimental Intracerebral Hemorrhage

Cited by 90 publications

References 34 publications

Microglia Activation and Polarization After Intracerebral Hemorrhage in Mice: the Role of Protease-Activated Receptor-1

Microglia Activation and Polarization After Intracerebral Hemorrhage in Mice: the Role of Protease-Activated Receptor-1

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

MRI Characterization in the Acute Phase of Experimental Subarachnoid Hemorrhage

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