RIPK3/MLKL-Mediated Neuronal Necroptosis Modulates the M1/M2 Polarization of Microglia/Macrophages in the Ischemic Cortex

Yang, Jiping; Zhao, Yumin; Zhang, Li; Fan, Hong; Qi, Chuchu; Zhang, Kun; Liu, Xinyu; Lin, Fang; Chen, Siwei; Wang, Mengmeng; Kuang, Fang; Wang, Shaobin; Wu, Shengxi

doi:10.1093/cercor/bhy089

Cited by 102 publications

(76 citation statements)

References 50 publications

(58 reference statements)

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“…65 Manipulation of this microglial/macrophage polarization is a neuroprotective strategy after stroke. 66 In a recent publication, Yang et al 67 demonstrated a link between necroptosis and the M1/M2 polarization of the ischemic cortex of the brain. The authors discovered that without RIPK3 or MLKL, both microglia and macrophages polarized to the M2 phenotype in the ischemic cortex.…”

Section: Strokementioning

confidence: 99%

Necroptosis in the Pathophysiology of Disease

Khoury

Gupta

Franco

et al. 2020

The American Journal of Pathology

211

149

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Section: Strokementioning

confidence: 99%

Necroptosis in the Pathophysiology of Disease

Khoury

Gupta

Franco

et al. 2020

The American Journal of Pathology

211

149

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“…Focal cortical ischemia was induced by photothrombosis of the cortical microvessels as described previously (Yu et al, 2015;Yang et al, 2018). Rose bengal (Sigma, Cat# 330000) was injected intraperitoneally (ip.)…”

Section: Photochemical Ischemia and Mouse Treatmentmentioning

confidence: 99%

Astragaloside IV Exerts Cognitive Benefits and Promotes Hippocampal Neurogenesis in Stroke Mice by Downregulating Interleukin-17 Expression via Wnt Pathway

et al. 2020

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Background: Stroke remains a leading cause of adult disability and the demand for stroke rehabilitation services is growing, and Astragaloside IV (As IV), a primary bioactive compound of Radix Astragali: Astragalus mongholicus Bunge (Fabaceae), may be a promising stroke therapy. Methods: To access the effect of As IV on adult mice after ischemic stroke, a photochemical ischemia model was established on C57BL/6 mice, which were intravenously administered As IV for three consecutive days later. And then the cognitive benefits and hippocampal neurogenesis were evaluated by Morris Water Maze (MWM) test, Golgi staining, and immunohistochemical staining in vivo and in vitro. Furthermore, to find out the underlying mechanism, interleukin-17 (IL-17) knockout (KO) mice were used, through RNA sequence (RNA-seq) analysis and immunohistochemistry. Then the mechanism of neurogenesis promoted by As IV was observed by western blot both in vivo and in vitro. Specifically, As IV, recombinant mouse IL-17A and IL-17F, and Wingless/integrated (Wnt)-expressing virus was administered respectively in neural stem cells (NSCs), and then their diameters and protein expression of Nestin, IL-17, and Wnt pathway relevant protein, were measured in vitro. Results: Administering As IV resulted in significant amelioration of stroke-induced cognitive deficits. And more hippocampal neurons with normal morphology, significant increments in the length of the apical dendrites, and the density of their spines were observed in As IV-treated mice. Furthermore, the immunohistochemistry staining of DCX/ BrdU and Sox2/Nestin showed As IV could promote hippocampal neurogenesis and NSC proliferation after ischemic stroke, as well as in vitro. For the mechanism underlying, IL-17 expression was downregulated significantly by As IV treatment and knocking out IL-17 was associated with nervous regeneration and synapse repair according to the analysis of RNA-seq. Consistent to As IV treatment, knocking out IL-17 showed some promotion on hippocampal neurogenesis and proliferation of NSCs, with activating Wnt pathway after

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“…Increasing evidence suggests that microglia may be important cellular targets in ischemic stroke (Ma, Wang, Wang, & Yang, ; Rahimian et al, ). Intervening in microglia‐mediated inflammation has been considered as a prime strategy for the development of new ischemic stroke therapies (Lambertsen, Finsen, & Clausen, ; Qin et al, , ; Yang et al, ; Yew et al, ).…”

Section: Introductionmentioning

confidence: 99%

Kellerin alleviates cognitive impairment in mice after ischemic stroke by multiple mechanisms

Zhang

Jiang

et al. 2020

Phytotherapy Research

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Ischemic stroke is a global disease with high disability and mortality rates. Cognitive impairment is one of the major clinical features of ischemic stroke, and microglia‐mediated inflammation has been shown to be an important contributor to the pathogenesis of ischemic stroke. Kellerin, extracted from Ferula sinkiangensis, was previously shown to inhibit microglial activation and exert a strong anti‐neuroinflammatory effect. However, there is no report of the potential therapeutic effect of kellerin on ischemic stroke by targeting microglial cells. In this study, we wanted to examine the effects of kellerin on ischemic stroke in the bilateral common carotid artery occlusion (BCCAO) model and the lipopolysaccharide (LPS)‐activated microglia model. We found that kellerin alleviated cognitive impairment, decreased neuronal loss, suppressed microglial activation, and transformed microglia from the pro‐inflammatory M1 phenotype to the anti‐inflammatory M2 phenotype in BCCAO mice. Moreover, in in vitro studies, we found that kellerin regulated microglial polarization and inhibited the NLRP3 and MAPK signaling pathways after LPS treatment. These findings provide a new understanding of the function of kellerin in ischemic stroke, and suggest that kellerin could be a potential therapeutic agent for the treatment of ischemic stroke.

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RIPK3/MLKL-Mediated Neuronal Necroptosis Modulates the M1/M2 Polarization of Microglia/Macrophages in the Ischemic Cortex

Cited by 102 publications

References 50 publications

Necroptosis in the Pathophysiology of Disease

Necroptosis in the Pathophysiology of Disease

Astragaloside IV Exerts Cognitive Benefits and Promotes Hippocampal Neurogenesis in Stroke Mice by Downregulating Interleukin-17 Expression via Wnt Pathway

Kellerin alleviates cognitive impairment in mice after ischemic stroke by multiple mechanisms

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