RETRACTED: Regulatory T cells ameliorate intracerebral hemorrhage-induced inflammatory injury by modulating microglia/macrophage polarization through the IL-10/GSK3β/PTEN axis

Zhou, Kai; Zhong, Qi; Wang, Yan Chun; Xiong, Xiao Yi; Meng, Zhao You; Zhao, Ting; Zhu, Wen; Liao, Mao Fan; Wu, Li Rong; Yang, Yuan; Liu, Juan; Duan, Chun Mei; Li, Jie; Gong, Qiu Wen; Liu, Liang; Yang, Mei; Xiong, Ao; Wang, Jian; Yang, Qing

doi:10.1177/0271678x16648712

Cited by 162 publications

(153 citation statements)

References 46 publications

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“…In particular, the role of IL-10 and IL-10 signaling in ICH is largely unclear. Although we cannot formally rule out the effect of rosiglitazone on regulatory T cell-derived IL-10 in our study, previous studies from our lab have shown that IL-10 released from regulatory T cell can regulate microglia alternative phenotype (Zhou et al, 2016). When we injected IL-10, a cytokine which has shown to polarize MMΦ toward alternative activation, intraventricularly into the ICH mice, we found a reduction of hematoma volume at day 3 post-ICH.…”

Section: Discussionmentioning

confidence: 87%

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

Chang

Wan

et al. 2017

Neurobiology of Disease

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113

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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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Section: Discussionmentioning

confidence: 87%

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

Chang

Wan

et al. 2017

Neurobiology of Disease

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113

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“…Ten mice from each group were sacrificed for Western blot analysis on day 7 after MCAO as described previously [31–33]. Briefly, mice were deeply anesthetized with an i.p.…”

Section: Methodsmentioning

confidence: 99%

Alpha-7 Nicotinic Receptor Signaling Pathway Participates in the Neurogenesis Induced by ChAT-Positive Neurons in the Subventricular Zone

Wang

et al. 2017

Transl. Stroke Res.

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Choline acetyltransferase-positive (ChAT+) neurons within the subventricular zone (SVZ) have been shown to promote neurogenesis after stroke in mice by secreting acetylcholine (ACh); however, the mechanisms remain unclear. Receptors known to bind ACh include the nicotinic ACh receptors (nAChRs), which are present in the SVZ and have been shown to be important for cell proliferation, differentiation, and survival. In this study, we investigated the neurogenic role of the α7 nAChR in a mouse model of middle cerebral artery occlusion (MCAO) by using α7 nAChR inhibitor methyllycaconitine. Mice subjected to MCAO exhibited elevated expression of cytomembrane and nuclear fibroblast growth factor receptor 1 (FGFR1), as well as increased expression of PI3K, pAkt, doublecortin (DCX), polysialylated neuronal cell adhesion molecule (PSA-NCAM), and mammalian achaete-scute homolog 1 (Mash1). MCAO mice also had more GFAP/BrdU-positive cells and DCX-positive cells in the SVZ than did the sham-operated group. Methyllycaconitine treatment increased cytomembrane FGFR1 expression and GFAP/BrdU-positive cells, upregulated the levels of PI3K and pAkt, decreased nuclear FGFR1 expression, decreased the number of DCX-positive cells, and reduced the levels of DCX, PSA-NCAM, and Mash1 in the SVZ of MCAO mice compared with levels in vehicle-treated MCAO mice. MCAO mice treated with α7 nAChR agonist PNU-282987 exhibited the opposite effects. Our data show that α7 nAChR may decrease the proliferation of neural stem cells and promote differentiation of existing neural stem cells after stroke. These results identify a new mechanism of SVZ ChAT+ neuron-induced neurogenesis.

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“…CD45 is helpful in this scenario because it is more highly expressed in monocytes than in microglia. Thus, CD45 expression levels can be used to separate these two cell types using flow cytometry: CD45 Int CD11b + cells are microglia and CD45 Hi CD11b + cells are macrophages 45–47 .…”

Section: Microgliamentioning

confidence: 99%

“…Complement C3a and C5a are thought to be involved in neuro-inflammation 72 , neutrophil recruitment 73 and blood–brain barrier disruption 45 . ICH-induced microglial activation, as assessed by immunoreactivity to an anti-CD11b and anti-CD11c dual-specificity antibody (OX42), was reduced in C3-deficient mice compared with wild-type controls 74 .…”

Section: Microgliamentioning

confidence: 99%

Modulators of microglial activation and polarization after intracerebral haemorrhage

et al. 2017

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Intracerebral haemorrhage (ICH) is the most lethal subtype of stroke but currently lacks effective treatment. Microglia are among the first non-neuronal cells on the scene during the innate immune response to ICH. Microglia respond to acute brain injury by becoming activated and developing classic M1-like (proinflammatory) or alternative M2-like (anti-inflammatory) phenotypes. This polarization implies as yet unrecognized actions of microglia in ICH pathology and recovery, perhaps involving microglial production of proinflammatory or anti-inflammatory cytokines and chemokines. Furthermore, alternatively activated M2-like microglia might promote phagocytosis of red blood cells and tissue debris, a major contribution to haematoma clearance. Interactions between microglia and other cells modulate microglial activation and function, and are also important in ICH pathology. This Review summarizes key studies on modulators of microglial activation and polarization after ICH, including M1-like and M2-like microglial phenotype markers, transcription factors and key signalling pathways. Microglial phagocytosis, haematoma resolution, and the potential crosstalk between microglia and T lymphocytes, neurons, astrocytes, and oligodendrocytes in the ICH brain are described. Finally, the clinical and translational implications of microglial polarization in ICH are presented, including the evidence that therapeutic approaches aimed at modulating microglial function might mitigate ICH injury and improve brain repair.

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RETRACTED: Regulatory T cells ameliorate intracerebral hemorrhage-induced inflammatory injury by modulating microglia/macrophage polarization through the IL-10/GSK3β/PTEN axis

Cited by 162 publications

References 46 publications

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

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

Alpha-7 Nicotinic Receptor Signaling Pathway Participates in the Neurogenesis Induced by ChAT-Positive Neurons in the Subventricular Zone

Modulators of microglial activation and polarization after intracerebral haemorrhage

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