Treatment targets for M2 microglia polarization in ischemic stroke

2018 ◽  
Vol 105 ◽  
pp. 518-525 ◽  
Author(s):  
Ji wang ◽  
Hongyi xing ◽  
Lin wan ◽  
Xingjun jiang ◽  
Chen wang ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Treatment Targets ◽  
M2 Microglia ◽  
Microglia Polarization

Minocycline Promotes Functional Recovery in Ischemic Stroke by Modulating Microglia Polarization Through STAT1/STAT6 Pathways

2021 ◽  
Author(s):  
Yunnan Lu ◽  
Mingming Zhou ◽  
Yun Li ◽  
Yan Li ◽  
Ye Hua ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Functional Recovery ◽  
Neuronal Injury ◽  
Reactive Gliosis ◽  
Rotarod Test ◽  
M2 Microglia ◽  
Microglia Polarization ◽  
M1 Phenotype ◽  
Corner Turning ◽  
Turning Test

Abstract BackgroundIncreasing evidence suggests that microglia experience two distinct phenotypes after acute ischemic stroke (AIS): a deleterious M1 phenotype and a neuroprotective M2 phenotype. Promoting the phenotype shift of M1 microglia to M2 microglia is thought to improve functional recovery after AIS. Minocycline, a tetracycline antibiotic, can improve functional recovery after cerebral ischemia in pre-clinical and clinical research. However, the role and mechanisms of minocycline in microglia polarization is unclear.MethodsUsing the transient middle cerebral artery occlusion - reperfusion (MCAO/R) model, we treated mice with saline or different minocycline concentration (10, 25, or 50 mg/kg, i.p., daily for 2 wk) at 24 h after reperfusion. Neurobehavioral evaluation, rotarod test, and corner turning test were carried out on day 14 after reperfusion. Then, neuronal injury, reactive gliosis, and microglia polarization were performed on day 7 following MCAO/R. Finally, we treated primary microglial cultures with LPS (Lipopolysaccharide; 100 ng/mL) plus IFN-γ (20 ng/mL) 24 h to induce M1 phenotype and observed the effects of minocycline on the M1/M2-related mRNAs and the STAT1/STAT6 pathway.ResultsWe found that a 14-day treatment with minocycline increased the survival rate and promoted functional outcomes evaluated with neurobehavioral evaluation, rotarod test, and corner turning test. Meanwhile, minocycline reduced the brain infarct volume, alleviated neuronal injury, and suppressed reactive gliosis on day 7 following MCAO/R. Moreover, we observed an additive effect of minocycline on microglia polarization to the M1 and M2 phenotypes in vivo and in vitro. In the primary microglia, we further found that minocycline prevented neurons from OGD/R-induced cell death in neuron-microglia co-cultures via regulating M1/M2 microglia polarization through the STAT1/STAT6 pathway. ConclusionMinocycline promoted microglial M2 polarization and inhibited M1 polarization, leading to neuronal survival and neurological functional recovery. The findings deepen our understanding of the mechanisms underlying minocycline-mediated neuroprotection in AIS.

Abstract T P80: Inhibition of Ezh2 Leads to Decreased M1 and Enhanced M2 Microglia Phenotypes

Stroke ◽  
2015 ◽  
Vol 46 (suppl_1) ◽  
Author(s):  
Edward Koellhoffer ◽  
Jeremy Grenier ◽  
Rodney Ritzel ◽  
Louise McCullough
Keyword(s):  
Ischemic Stroke ◽  
Pcr Analysis ◽  
M2 Polarization ◽  
M2 Microglia ◽  
M1 Polarization ◽  
Glial Cultures ◽  
M2 Response ◽  
M1 Phenotype ◽  
Cayman Chemical ◽  
M2 Phenotype

Background: Ischemic stroke results in the activation of microglia, which may polarize toward a pro-inflammatory (M1) phenotype or an anti-inflammatory, neuroprotective (M2) phenotype. Thus, simultaneously suppressing the M1 response and promoting the M2 response could be beneficial in the treatment of stroke. Recently, the epigenetic modulator Jmjd3 has been shown to be essential for M2 polarization. However, Jmjd3 is antagonized by Ezh2 which is associated with M1 polarization. Thus, we hypothesized that inhibition of Ezh2 tilts the balance between Jmjd3 and Ezh2, thereby enhancing polarization toward an M2 phenotype and improved outcome in ischemic stroke. Methods: Mixed glial cultures were isolated from P0.5-P2 C57BL/6J mice and cultured for 14 days before microglial isolation. Microglia were rested for 24 hours before treatment every other day with 6uM GSK343 (Cayman Chemical) or DMSO vehicle control. After 7 days, microglia were stimulated with LPS or IL-4 and RNA was isolated at 4hr and 24hr post-stimulation for qRT-PCR analysis. Results: LPS-induced IL6 and IL1B expression was significantly abrogated by 71% and 53%, respectively (p<0.05), at 24hr when Ezh2 was inhibited. Additionally, Ezh2 inhibition both increased baseline expression of M2-associated genes ARG1, CD206, and IRF4 by 196%, 257%, and 395%, respectively (p<0.05), and rescued their expression in the presence of LPS at 24hr (p<0.05) in which they were otherwise significantly down-regulated. Conclusion: Pharmacological inhibition of Ezh2 limits microglial M1 polarization and enhances M2 polarization.

scholarly journals Ginkgolide B Protects Against Ischemic Stroke Via Modulating Microglia Polarization in Mice

2016 ◽  
Vol 22 (9) ◽  
pp. 729-739 ◽  
Author(s):  
Zhao-Ma Shu ◽  
Xiao-Dong Shu ◽  
Hui-Qin Li ◽  
Yi Sun ◽  
Han Shan ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Ginkgolide B ◽  
Microglia Polarization

Abstract 44: Hdac3i Alleviated Ischemic Stroke Injury Through Modulating Aim2 Inflammasome and Microglia Polarization

Stroke ◽  
2017 ◽  
Vol 48 (suppl_1) ◽  
Author(s):  
Meijuan Zhang ◽  
Mingxu Xia ◽  
Qiuchen Zhao ◽  
Yun Xu
Keyword(s):  
Ischemic Stroke ◽  
Infarct Volume ◽  
Glucose Deprivation ◽  
Vehicle Group ◽  
Triphenyltetrazolium Chloride ◽  
Bv2 Cells ◽  
Severity Scores ◽  
Microglia Polarization

Background: Inflammasome in microglia are critical to elicit inflammatory cascades in ischemic stroke. Histone deacetylases 3 (HDAC3) regulate acetylation states of histone and non-histone proteins and could be a powerful regulator of inflammatory process in stroke. Methods: Primary microglia, BV2 cells subjected to oxygen glucose deprivation (OGD) or LPS stimulation were applied to mimic inflammatory response in vitro . Middle cerebral artery occlusion (MCAO) model were applied to mimic acute stroke in vivo . Ischemic infarct volume and neurological functions were evaluated through 2,3,5-triphenyltetrazolium chloride (TTC) staining and Neurological Severity Scores (NSS) respectively. Expression of HDAC3, AIM2 inflammasome were detected by western blotting, PCR. Immunofluorescence was used to detect M1/M2 polarization. Luciferase activity of absent in melanoma 2 (AIM2) reporter promoter constructs was measured by fluorospectrophotometer. AIM2 knockdown and over-expression leti-virus were constructed to decrease or increase AIM2 expression. HDAC3 inhibitor RGFP966 was used to inhibit acetylation activity of HDAC3. Results: HDAC3 is widely distributed in cerebral cortex, lateral ventricular , hippocampus, cerebellar cortex ; HDAC3 and AIM2 expression were enhanced in LPS stimulated-microglia and MCAO model. A marked stimulatory effect of RGFP966 on H3K9Ac was observed in nuclear extracts form BV2 cells at the dosage of 15 uM. Treatment of RGFP966 increased both IL-4-stimulated expression of Ym-1 and CD206 at 4 h, 10 h, 24 h, 48 h. AIM2, NLRP-1 and NLRP3 significantly increased in MCAO+Vehicle group compared to sham group, but decreased in MCAO+RGFP966 group. RGFP966 inhibited the elevation of circulatory IL-18 and IL-1β induced by stroke. RGFP966 decreased infracted size and alleviated neurological deficit. Conclusions: HDAC3i alleviated ischemic stroke injury through modulating AIM2 inflammasome and microglia polarization. Selective HDAC3 inhibitor-RGFP966 could be a potential medication for combating ischemic brain injury.

Neuregulin-1 Regulates the Conversion of M1/M2 Microglia Phenotype via ErbB4-dependent Inhibition of the NF-κB Pathway

2021 ◽  
Author(s):  
Yuqi Ma ◽  
Peixia Fan ◽  
Rui Zhao ◽  
Yinghua Zhang ◽  
Xianwei Wang ◽  
...  
Keyword(s):  
Inflammatory Factors ◽  
Neuregulin 1 ◽  
Microglial Polarization ◽  
M2 Microglia ◽  
Tnf Α ◽  
Microglia Polarization ◽  
Dependent Inhibition ◽  
The Central Nervous System ◽  
The Relationship

Abstract BackgroundThe inflammatory response caused by microglia in the central nervous system plays an important role in Alzheimer's disease. Neuregulin-1 (NRG1) is a member of the neuregulin family and has been demonstrated to have anti-inflammatory properties. The relationship between NRG1, microglia phenotype and neuroinflammation remains unclear.Materials and MethodsBV2 cells were used to examine the mechanism of NRG1 in regulating microglia polarization. Neuronal apoptosis, inflammatory factors TNF-α and iNOS, microglia polarization, ErbB4 and NF-κB p65 expression were assessed.ResultsWe found that exogenous NRG1 treatment or overexpression improved microglial activity and reduced the secretion of the inflammatory factors TNF-α and iNOS in vitro. The expression of Bax in SH-SY5Y neuron cells incubated with medium collected from the NRG1 treatment group decreased. Additionally, our study showed that NRG1 treatment reduced the levels of the M1 microglia markers CD120 and iNOS and increased the levels of the M2 microglia markers CD206 and Arg-1. Furthermore, we observed that NRG1 treatment attenuated Aβ-induced NF-κB activation and promoted the expression of p-ErbB4 and that knockdown of ErbB4 abrogated the effects of NRG1 on NF-κB, Bax levels and M2 microglial polarization. ConclusionNRG1 inhibits the release of inflammatory factors in microglia and regulates the switching of the M1/M2 microglia phenotype, most likely via ErbB4-dependent inhibition of the NF-κB pathway.

XQ-1H protects against ischemic stroke by regulating microglia polarization through PPARγ pathway in mice

2018 ◽  
Vol 57 ◽  
pp. 72-81 ◽  
Author(s):  
Rui Liu ◽  
Junjian Diao ◽  
Shucheng He ◽  
Binbin Li ◽  
Yuxiang Fei ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Microglia Polarization

scholarly journals Normobaric intermittent hypoxic training regulates microglia phenotype and enhances phagocytic activity

2020 ◽  
Vol 245 (8) ◽  
pp. 740-747
Author(s):  
Genell Tantingco ◽  
Myoung-Gwi Ryou
Keyword(s):  
Ischemic Stroke ◽  
Phagocytic Activity ◽  
Glucose Deprivation ◽  
Recovery Process ◽  
Oxygen Glucose Deprivation ◽  
Intermittent Hypoxic Training ◽  
Hypoxic Training ◽  
Pathological Conditions ◽  
Microglia Polarization

The microglia are the resident immune cells in the central nerve system. In the various pathological conditions, prolonged activated microglia could deteriorate brain damage. The regulation of the microglia polarization should be considered in developing an intervention for ischemic stroke patients. Normobaric intermittent hypoxic training protects the brain from intensive ischemic stresses. This study examined the role of intermittent hypoxic training in the regulation of microglia polarization that occurs in the in vitro model of oxygen–glucose deprivation (OGD)–reoxygenation. EOC20 were assigned to the following groups; (1) Normoxia, (2) oxygen–glucose deprivation–reoxygenation, (3) intermittent hypoxic training, (4) oxygen–glucose deprivation–reoxygenation +  intermittent hypoxic training; 24 h after the intermittent hypoxic training, microglia were harvested to perform the following experiments; cell viability (Calcein AM and LDH activity assay), quantification of proteins (Western blot), cytokine (ELISA), and reactive oxygen species (ROS) (H2DCFDA assays), phagocytic activity by using latex beads coated with FITC, and cell phenotype (immunocytochemistry and flow cytometric analysis, and immunoblot CD206 (M2)). One-way ANOVA with Tukey’s post hoc test was used for the statistical analysis. Oxygen–glucose deprivation/reoxygenation decreases cell viability to 50% of normoxia. Intermittent hypoxic training protects the microglia from oxygen–glucose deprivation/reoxygenation stress. Intermittent hypoxic training regulates the polarization of the microglial phenotype toward anti-inflammatory type M2 (vs. oxygen–glucose deprivation and reoxygenation). Intermittent hypoxic training increases phagocytic activity (about 12 folds) vs. normoxia. ROS in the oxygen–glucose deprivation/reoxygenation group is increased, but intermittent hypoxic training lowers the ROS generation by oxygen–glucose deprivation/reoxygenation. The protein content of the toll-like receptor (TLR2) was significantly elevated in the oxygen–glucose deprivation and reoxygenation group, and intermittent hypoxic training lowered to normoxia level. Anti-inflammatory cytokines, such as IL-10 and IL-4, were significantly increased in the intermittent hypoxic training groups. Due to the effect of intermittent hypoxic training on the microglia phenotype, intermittent hypoxic training could be considered as an effective intervention in the treatment or rehabilitation program for the ischemic stroke victims. Impact statement The effects of intermittent hypoxic training or conditioning on many pathological conditions have been widely investigated. One of the pathological conditions dealt with intermittent hypoxic training is ischemic stroke. Well-known mechanisms of intermittent hypoxia-induced protection are related to increased energy metabolism and the enhanced antioxidant effects. In the last decades, the role of microglia in the progress of ischemic stroke-related brain damage has been focused. The dual-edge function of microglia indicates that the microglia-mediated inflammatory response is definitely beneficial in the early stage of ischemic stroke, but long-term activation of microglia is rather detrimental during the recovery process. The effect of IHT on microglia polarization is not investigated. This study focused on whether IHT regulates the polarization of microglia without dampening its classic phagocytic function. This study will provide pivotal information regarding the effects of IHT on the long-term effects on the recovery process from ischemic stroke.

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