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

Wan, Shu; Cheng, Yingying; Jin, Hang; Guo, Dewei; Hua, Ya; Keep, Richard F.; Xi, Guohua

doi:10.1007/s12975-016-0472-8

Cited by 128 publications

(107 citation statements)

References 46 publications

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“…In a blood injection model of ICH (Wan et al, 2016), global expression of CD16 and iNOS was increased after 4 h, and CD206 and YM-1 expression was increased after 24 h. On day 4 post-ICH, mRNA levels of proinflammatory cytokines were upregulated, whereas M2 markers did not exhibit a significant change. However, the time course of change in specific microglial M1-/M2-like polarization is still unknown.…”

Section: Discussionmentioning

confidence: 99%

Pinocembrin protects hemorrhagic brain primarily by inhibiting toll-like receptor 4 and reducing M1 phenotype microglia

Lan

Han

et al. 2017

Brain, Behavior, and Immunity

180

153

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Neuroinflammation is a major contributor to intracerebral hemorrhage (ICH) progression, but no drug is currently available to reduce this response and protect against ICH-induced injury. Recently, the natural product pinocembrin has been shown to ameliorate neuroinflammation and is undergoing a phase II clinical trial for ischemic stroke treatment. In this study, we examined the efficacy of pinocembrin in an ICH model, and further examined its effect on microglial activation and polarization. In vivo, pinocembrin dose-dependently reduced lesion volume by 47.5% and reduced neurologic deficits of mice at 72 h after collagenase-induced ICH. The optimal dose of pinocembrin (5 mg/kg) suppressed microglial activation as evidenced by decreases in CD68-positive microglia and reduced proinflammatory cytokines tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6. Pinocembrin also reduced the number of classically activated M1-like microglia without affecting M2-like microglia in the perilesional region. Additionally, pinocembrin decreased the expression of toll-like receptor (TLR)4 and its downstream target proteins TRIF and MyD88. The protection by pinocembrin was lost in microglia-depleted mice and in TLR4lps-del mice, and pinocembrin failed to decrease the number of M1-like microglia in TLR4lps-del mice. In lipopolysaccharide-stimulated BV-2 cells or primary microglia, pinocembrin decreased M1-related cytokines and markers (IL-1β, IL-6, TNF-α, and iNOS), NF-κB activation, and TLR4 expression, but it did not interfere with TLR4/MyD88 and TLR4/TRIF interactions or affect microglial phagocytosis of red blood cells. Inhibition of the TLR4 signaling pathway and reduction in M1-like microglial polarization might be the major mechanism by which pinocembrin protects hemorrhagic brain. With anti-inflammatory properties, pinocembrin could be a promising new drug candidate for treating ICH and other acute brain injuries.

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Section: Discussionmentioning

confidence: 99%

Pinocembrin protects hemorrhagic brain primarily by inhibiting toll-like receptor 4 and reducing M1 phenotype microglia

Lan

Han

et al. 2017

Brain, Behavior, and Immunity

180

153

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“…Western blot analysis was performed as previously described (23, 36, 38). Briefly, rats were perfused with 0.1mmol/L phosphate buffered saline (pH 7.4) after euthanasia and the ipsi- and contralateral cortex, white matter (corpus callosum) and basal ganglia were sampled.…”

Section: Methodsmentioning

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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“…Therefore, the effect of DRα1-MOG-35-55 to shift microglia/macrophage polarity toward a beneficial M2-like phenotype may partially contribute to the protection of the ischemic brain. Since microglia/macrophage phenotype change is also common in other forms of CNS injuries [43], the effect of DRα1-MOG-35-55 on other neurological disorders such as intracerebral hemorrhage needs to be examined.…”

Section: Discussionmentioning

confidence: 99%

DRα1-MOG-35-55 Reduces Permanent Ischemic Brain Injury

Wang

et al. 2016

Transl. Stroke Res.

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Stroke induces a catastrophic immune response that involves the global activation of peripheral leukocytes, especially T cells. The HLA-DRα1 domain linked to MOG-35-55 peptide (DRα1-MOG-35-55) is a partial major histocompatibility complex II (MHC II) construct which can inhibit neuroantigen-specific T cells and block binding of the cytokine/chemokine macrophage migration inhibitory factor (MIF) to its CD74 receptor on monocytes and macrophages. Here, we evaluated the therapeutic effect of DRα1-MOG-35-55 in a mouse model of permanent distal middle cerebral artery occlusion (dMCAO). DRα1-MOG-35-55 was administered to WT C57BL/6 mice by subcutaneous injection starting 4h after the onset of ischemia followed by 3 daily injections. We demonstrated that DRα1-MOG-35-55 post-treatment significantly reduced brain infarct volume, improved functional outcomes and inhibited the accumulation of CD4+ and CD8+ T cells and expression of pro-inflammatory cytokines in the ischemic brain 96h after dMCAO. In addition, DRα1-MOG-35-55 treatment shifted microglia/macrophages in the ischemic brain to a beneficial M2 phenotype without changing their total numbers in the brain or blood. This study demonstrates for the first time the therapeutic efficacy of the DRα1-MOG-35-55 construct in dMCAO across MHC class II barriers in C57BL/6 mice. This MHC independent effect obviates the need for tissue typing and will thus greatly expedite treatment with DRα1-MOG-35-55 in human stroke subjects. Taken together, our findings suggest that DRα1-MOG-35-55 treatment may reduce ischemic brain injury by regulating post-stroke immune responses in the brain and the periphery.

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

Cited by 128 publications

References 46 publications

Pinocembrin protects hemorrhagic brain primarily by inhibiting toll-like receptor 4 and reducing M1 phenotype microglia

Pinocembrin protects hemorrhagic brain primarily by inhibiting toll-like receptor 4 and reducing M1 phenotype microglia

MRI Characterization in the Acute Phase of Experimental Subarachnoid Hemorrhage

DRα1-MOG-35-55 Reduces Permanent Ischemic Brain Injury

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