Exosomes from LPS-stimulated macrophages induce neuroprotection and functional improvement after ischemic stroke by modulating microglial polarization

Zheng, Yan; He, Ruyi; Wang, Peng; Shi, Yijie; Zhao, Liang; Liang, Jia

doi:10.1039/c8bm01449c

Cited by 147 publications

(120 citation statements)

References 35 publications

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“…in addition, choi et al (53) confirmed that M2 microglia promoted the proliferation and neuronal differentiation of neural stem/progenitor cells in the ipsilateral subventricular zone following ischemic stroke through upregulating the expression levels of TGF-α; this may provide an effective therapy for neurogenesis. additionally, macrophages recruited by microglia were identified to enhance M2 microglia polarization and improve stroke outcome (54,55). Similar to M1 microglia, besides from ischemic stroke, M2 microglia activation occurs in numerous other types of neurological disease; for example, in both spinal cord injury and intracerebral hemorrhage mouse models, M2 microglia were identified to be activated, which released anti-inflammatory cytokines downstream of caMP response element-binding protein (creB)-associated signaling pathways (56,57).…”

Section: Microgliamentioning

confidence: 99%

Modulators of microglia activation and polarization in ischemic stroke (Review)

et al. 2020

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ischemic stroke is one of the leading causes of mortality and disability worldwide. However, there is a current lack of effective therapies available. as the resident macrophages of the brain, microglia can monitor the microenvironment and initiate immune responses. in response to various brain injuries, such as ischemic stroke, microglia are activated and polarized into the proinflammatory M1 phenotype or the anti-inflammatory M2 phenotype. The immunomodulatory molecules, such as cytokines and chemokines, generated by these microglia are closely associated with secondary brain damage or repair, respectively, following ischemic stroke. it has been shown that M1 microglia promote secondary brain damage, whilst M2 microglia facilitate recovery following stroke. in addition, autophagy is also reportedly involved in the pathology of ischemic stroke through regulating the activation and function of microglia. Therefore, this review aimed to provide a comprehensive overview of microglia activation, their functions and changes, and the modulators of these processes, including transcription factors, membrane receptors, ion channel proteins and genes, in ischemic stroke. The effects of autophagy on microglia polarization in ischemic stroke were also reviewed. Finally, future research areas of ischemic stroke and the implications of the current knowledge for the development of novel therapeutics for ischemic stroke were identified. Contents 1. introduction 2. Microglia 3. Modulatory mechanisms of microglia polarization 4. autophagy 5. conclusions

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Section: Microgliamentioning

confidence: 99%

Modulators of microglia activation and polarization in ischemic stroke (Review)

et al. 2020

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“…On these basis, we further considered the activation of microglia in vitro and in vivo. The activated microglia after ischemia details a dual function of promoting inflammation and anti-inflammation due to its polarization to M1/M2 phenotype conversion [6,40,41]. We found that rhTrx-1 treatment increased M2 phenotype microglia and decreased M1 phenotype after OGD procedure.…”

Section: Discussionmentioning

confidence: 68%

RhTrx-1 ameliorates miroglial neuroinflammation after cerebral ischemic stroke

Jiao¹,

Wang²,

Zhang³

et al. 2020

Preprint

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Background Microglia are rapidly activated after ischemic stroke and participate in the occurrence of neuroinflammation, which exacerbates the injury of ischemic stroke. Receptor Interacting Serine Threonine Kinase 1 (RIPK1) is thought to be involved in the development of inflammatory responses, but its role in ischemic microglia remains unclear. Here, we applied recombinant human thioredoxin-1 (rhTrx-1), a potential neuroprotective agent, to explore the role of rhTrx-1 in inhibiting RIPK1-mediated neuroinflammatory responses in microglia. Method Middle cerebral artery occlusion (MCAO) and Oxygen and glucose deprivation (OGD) were conducted for in vivo and in vitro experimental stroke models. The expression of RIPK1 in microglia after ischemia was examined. The inflammatory response of microglia was analyzed after treatment with rhTrx-1 and Necrostatin-1 (Nec-1, inhibitors of RIPK1), and the mechanisms were explored. In addition, the effects of rhTrx-1 on neurobehavioral deficits and cerebral infarct volume were examined. Results RIPK1 expression was detected in microglia after ischemia. Molecular docking results showed that rhTrx-1 could directly bind to RIPK1. In vitro experiments found that rhTrx-1 reduced necroptosis, mitochondrial membrane potential damage, Reactive oxygen species (ROS) accumulation and NLR Family, pyrin domain-containing 3 protein (NLRP3) inflammasome activation by inhibiting RIPK-1 expression, and regulated microglial M1/M2 phenotypic changes, thereby reducing the release of inflammatory factors. Consistently, in vivo experiments found that rhTrx-1 treatment attenuated cerebral ischemic injury by inhibiting the inflammatory response. Conclusion Our study demonstrates the role of RIPK1 in microglia-arranged neuroinflammation after cerebral ischemia. Administration of rhTrx-1 provides neuroprotection in ischemic stroke-induced microglial neuroinflammation by inhibiting RIPK1 expression.

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“…The speci c steps for preparing and purifying Exos and LPS-Exos in vitro are as previously described [6,11].When the content of RAW264.7 cells reached 90% in a 150 mm cell culture dish, the culture medium was replaced by the FBS deleted by exosomes (1 x DMEM, 10% heat inactivated FBS deleted by ultra ltration).In order to prepare LPS-Exos, LPS (100 ng / ml) was added to the cell culture dish to stimulate the growth of RAW264.7 cells, and the culture continued for 24 hours.The supernatant of cell culture was collected by centrifuge tube,The mixture was then centrifuged at 4 ° C for 10 minutes at 2000 g and at 10000 g for 30 minutes to remove cells and debris, then ltered using a 0.22 µ M lter.Finally, the collected supernatant was transferred to a new ultracentrifuge (Hitachi, Koki, Co., Ltd, Japan), centrifuged at 4 ° C for 1.5 h at 120000 g, and then the supernatant was discarded to collect the transparent sediment at the bottom of the centrifuge tube to obtain the exosomes from LPS stimulated macrophages.…”

Section: Preparation and Puri Cation Of Exosomes From Lpsstimulated Mmentioning

confidence: 99%

“…Exosomes are double-layer nanospheres with 40-150 nm diameter, which contain miRNAs, mRNAs and proteins and can be secreted by different cell types [4,6].Exosomes can enter the target cells and release the contents of the inclusions through recognition of speci c antibodies on the target cell membrane, direct fusion, endocytosis, etc., and mediate information exchange between cells, so as to play their biological functions [7].A large number of studies have shown that the exosomes secreted by macrophages stimulated by lipopolysaccharide (LPS) contain more cytokines and miRNAs, and regulate the in ammatory response by transforming early pro-in ammatory gene transcription into antiin ammatory gene transcription [8,9].Meanwhile, according to reports, LPS stimulated exosomes secreted by macrophages are involved in the pathogenesis of various diseases and play a protective role by inhibiting in ammatory response, such as cerebral ischemia / reperfusion injury, pulmonary brosis and various metabolic diseases [10][11][12].…”

Section: Introductionmentioning

confidence: 99%

LPS-stimulated Macrophage Exosomes Inhibit Inflammation by Activating the Nrf2 / HO-1 Defense Pathway and Promote Wound Healing in Diabetic Rats

Tian

et al. 2020

Preprint

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Background:Impaired wound healing is one of the important complications of diabetes. However, the specific pathogenesis is still unclear, and there is no effective treatment. Macrophages pretreated with chemical or biological factors may increase the biological activity of macrophage-derived exosomes, which is expected to become a new effective treatment method. The purpose of this study was to investigate whether the exosomes secreted by macrophages pretreated with lipopolysaccharide (LPS) have better anti-inflammatory and angiogenic abilities in the treatment of diabetic wound healing and their underlying molecular mechanisms.Methods:In this study, macroscopical, biochemical, histological, immunofluorescence and molecular biology methods were used to evaluate the potential protective mechanism and effect of lipopolysaccharide stimulated macrophage exosomes (LPS-Exos) on wound healing in streptozotocin induced hyperglycemia rats.In the in vivo experiment, the percentages of wound closure and contraction were compared and analyzed on the 7th, 14th, and 21st day after treatment by grouping treatments with different concentrations of LPS-Exos.At the same time, hematoxylin and eosin staining (HE), Masson staining, immunofluorescence staining and Western blotting (WB) were used for histological analysis of the wound tissue on the 14th day after injury to evaluate the impact of different treatment methods on wound healing.In in vitro experiments, the ability of endothelial cells related to proliferation, migration, tube formation and the expression of vascular endothelial growth factor (VEGF) were tested.At the same time, in vivo and in vitro experiments, the effect of Nrf2/HO-1 signaling pathway on LPS-Exos in inhibiting inflammation and promoting angiogenesis was evaluated by using exosome-specific inhibitors.Results:LPS-Exos reduced the content of ROS and MDA in the wound tissue of hyperglycemic rats, increased the activity of SOD and the production of GSH-Px, activated the Nrf2/HO-1 pathway, inhibited the expression of inflammation-related proteins, and promoted blood vessels generate. The group given exosome inhibitors reversed this phenomenon.Conclusions: LPS-Exos may activate the Nrf2/HO-1 defense pathway, improve endothelial cell function, inhibit oxidative damage and inflammation, and promote wound healing in diabetic rats, thereby having the potential to treat diabetic skin defects.

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Exosomes from LPS-stimulated macrophages induce neuroprotection and functional improvement after ischemic stroke by modulating microglial polarization

Abstract: Inflammation occurs throughout the progression of cerebral ischemia/reperfusion and mediates myriads of pathological events following an ischemic insult.

Cited by 147 publications

References 35 publications

Modulators of microglia activation and polarization in ischemic stroke (Review)

Modulators of microglia activation and polarization in ischemic stroke (Review)

RhTrx-1 ameliorates miroglial neuroinflammation after cerebral ischemic stroke

LPS-stimulated Macrophage Exosomes Inhibit Inflammation by Activating the Nrf2 / HO-1 Defense Pathway and Promote Wound Healing in Diabetic Rats

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Exosomes from LPS-stimulated macrophages induce neuroprotection and functional improvement after ischemic stroke by modulating microglial polarization

Abstract: Inflammation occurs throughout the progression of cerebral ischemia/reperfusion and mediates myriads of pathological events following an ischemic insult.

Cited by 147 publications

References 35 publications

Modulators of microglia activation and polarization in ischemic stroke (Review)

Modulators of microglia activation and polarization in ischemic stroke (Review)

RhTrx-1 ameliorates miroglial neuroinflammation after cerebral ischemic stroke

LPS-stimulated Macrophage Exosomes Inhibit Inflammation by Activating the Nrf2&nbsp;/ HO-1 Defense Pathway and Promote Wound Healing in Diabetic Rats

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LPS-stimulated Macrophage Exosomes Inhibit Inflammation by Activating the Nrf2 / HO-1 Defense Pathway and Promote Wound Healing in Diabetic Rats