Brain-derived microparticles activate microglia/macrophages and induce neuroinflammation

Rong, Hongtao; Fan, Yueshan; Yang, Ming; Zhang, Baoliang; Sun, Dongdong; Zhao, Ziqi; Wang, Dong; Fan, Weidong; Wang, Jianhao; Gu, Gang; Li, Fanjian; Liu, Xilei; Rao, Chenxu; Chen, Huijiao; Wang, Yi; Tian, Ye; Zhang, Jianning

doi:10.1016/j.brainres.2018.05.015

Cited by 24 publications

(18 citation statements)

References 21 publications

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“…The protocol was similar to that used in previous research. 19 Membranes were incubated with anti-VE-cadherin (1:1000, Cell Signaling Technology, 2500, Danvers, Massachusetts, USA), anti-ZO-1 (1:1000, Cell Signaling Technology, 13,663, Danvers, Massachusetts, USA), anti-VCAM-1 (1:1000, Cell Signaling Technology, 13,662, Danvers, Massachusetts, USA), anti-ICAM-1 (1:1000, Abcam, ab18981) and anti-KLF-2 (1:250, Abcam, ab17008) antibodies. We then added horseradish peroxidase (HRP)-conjugated secondary IgG antibodies and incubated the membranes for 1 h at room temperature.…”

Section: Methodsmentioning

confidence: 99%

“…We performed immunofluorescence staining as previously described. 19 Cells were incubated overnight with a primary antibody specific for VE-cadherin (1:400, Cell Signaling Technology, 2500). Cells were then washed with PBS and incubated with an Alexa Fluor-conjugated anti-rabbit IgG antibody (1:500, Molecular Probes) for 1 h at room temperature.…”

Section: Methodsmentioning

confidence: 99%

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<p>Atorvastatin Combined with Low-Dose Dexamethasone Treatment Protects Endothelial Function Impaired by Chronic Subdural Hematoma via the Transcription Factor KLF-2</p>

Fan¹,

Wang²,

Rao³

et al. 2020

DDDT

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Objective Our previous study showed that the combination therapy with atorvastatin and low-dose dexamethasone protected endothelial cell function in chronic subdural hematoma (CSDH) injury. In this study, we aimed to investigate the mechanism underlying the effects of this combination therapy on CSDH-induced cell dysfunction. Methods Monocytes and endothelial cells were cocultured with CSDH patient hematoma samples to mimic the pathological microenvironment of CSDH. Monocytes (THP-1 cells) and endothelial cells (hCMEC/D3 cells) were cocultured in a transwell system for 24 h before stimulation with hematoma samples diluted in endothelial cell medium (ECM) at a 1:1 ratio. Tight junction markers were detected by Western blotting, PCR and immunofluorescence. hCMEC/D3 cells were collected for Western blot and PCR analyses to detect changes in the expression levels of vascular cell adhesion molecule (VCAM-1), intercellular adhesion molecule (ICAM-1), and Kruppel-like factor 2 (KLF-2). The IL-6, IL-10 and VEGF levels in the supernatant were measured by enzyme-linked immunosorbent assay (ELISA). Results KLF-2 expression in endothelial cells was decreased after stimulation with CSDH patient hematoma samples, but combination therapy with atorvastatin and low-dose dexamethasone reversed this trend. KLF-2 protected injured cells by increasing the expression of VE-cadherin and ZO-1; attenuating the expression of VCAM-1, ICAM-1, IL-6 and VEGF; and enhancing the expression of IL-10, all of which play pivotal roles in endothelial inflammation. Moreover, the effect of combination therapy with atorvastatin and low-dose dexamethasone was obviously reduced in endothelial cells with KLF-2 knockdown compared with normal cells. Conclusion Coculture with hematoma samples decreased KLF-2 expression in human cerebral endothelial cells. Combination therapy with atorvastatin and low-dose dexamethasone counteracted hematoma-induced KLF-2 suppression in human cerebral endothelial cells to attenuate robust endothelial inflammation and permeability. KLF-2 plays an important role in drug therapy for CSDH and may become the key factor in treatment and prognosis.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

<p>Atorvastatin Combined with Low-Dose Dexamethasone Treatment Protects Endothelial Function Impaired by Chronic Subdural Hematoma via the Transcription Factor KLF-2</p>

Fan¹,

Wang²,

Rao³

et al. 2020

DDDT

Self Cite

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“…Microglia-derived MPs and astrocyte-derived MPs contain and release the proinflammatory cytokine IL-1β, inflammasome components and MHCII proteins (47,48). Previous studies have found that enriched MPs from activated microglia in vitro or from mice brain are sufficient to initiate neuroinflammation following intracortical injection in naïve animals (16,17).…”

Section: Discussionmentioning

confidence: 99%

“…MPs play a key role in peripheral inflammatory progression, thrombosis, endothelial dysfunction, and angiogenesis (13)(14)(15). Microglial/macrophagederived MPs and BDMPs can increase brain inflammation in normal mice (16,17). MPs increase the permeability of bloodbrain barrier (BBB) (18) and BDMPs can migrate through the disrupted endothelial barrier (19).…”

Section: Introductionmentioning

confidence: 99%

Brain-Derived Microparticles (BDMPs) Contribute to Neuroinflammation and Lactadherin Reduces BDMP Induced Neuroinflammation and Improves Outcome After Stroke

et al. 2019

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Microparticles (MPs, ∼size between 0.1 and 1 mm) are lipid encased containers derived from intact cells which contain antigen from the parent cells. MPs are involved in intercellular communication and regulate inflammation. Stroke increases secretion of brain derived MP (BDMP) which activate macrophages/microglia and induce neuroinflammation. Lactadherin (Milk fat globule-EGF factor-8) binds to anionic phospholipids and extracellular matrices, promotes apoptotic cell clearance and limits pathogenic antigen cross presentation. In this study, we investigate whether BDMP affects stroke-induced neuroinflammation and whether Lactadherin treatment reduces stroke initiated BDMP-induced neuroinflammation, thereby improving functional outcome after stroke. Middle aged (8-9 months old) male C57BL/6J mice were subjected to distal middle cerebral artery occlusion (dMCAo) stroke, and BDMPs were extracted from ischemic brain 24 h after dMCAo by ultracentrifugation. Adult male C57BL/6J mice were subjected to dMCAo and treated via tail vein injection at 3 h after stroke with: (A) +PBS (n = 5/group); (B) +BDMPs (1.5 × 10 8 , n = 6/group); (C) +Lactadherin (400 µg/kg, n = 5/group); (D) +BDMP+Lactadherin (n = 6/group). A battery of neurological function tests were performed and mice sacrificed for immunostaining at 14 days after stroke. Blood plasma was used for Western blot assay. Our data indicate: (1) treatment of Stroke with BDMP significantly increases lesion volume, neurological deficits, blood brain barrier (BBB) leakage, microglial activation, inflammatory cell infiltration (CD45, microglia/macrophages, and neutrophils) into brain, inflammatory factor (TNFα, IL6, and IL1β) expression in brain, increases axon/white matter (WM) damage identified by decreased axon and myelin density, and increases inflammatory factor expression in the plasma when compared to PBS treated stroke mice; (2) when compared to PBS and Chen et al. BDMPs Mediate Neuroinflammation After Stroke BDMP treated stroke mice, Lactadherin and BDMP+Lactadherin treatment significantly improves neurological outcome, and decreases lesion volume, BBB leakage, axon/WM injury, inflammatory cell infiltration and inflammatory factor expression in the ischemic brain, respectively. Lactadherin treatment significantly increases anti-inflammatory factor (IL10) expression in ischemic brain and decreases IL1β expression in plasma compared to PBS and BDMP treated stroke mice, respectively. BDMP increases neuroinflammation and aggravates ischemic brain damage after stroke. Thus, Lactadherin exerts anti-inflammatory effects and improves the clearance of MPs to reduce stroke and BDMP induced neurological deficits.

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“…EVs can be divided into exosomes (30-100 nm), microparticles (100-1000 nm), and apoptotic bodies (500-4000 nm) because of their different diameters (Pan et al, 1985;Fauré et al, 2006;Maybruck et al, 2017;Karnati et al, 2019). The contents of EVs include proteins, lipids, and genetic material such as DNA, mRNA, and miRNA, and mediate intercellular communication (Faille et al, 2012;Rong et al, 2018;Mathieu et al, 2019). At present, EVs released under hypoxic conditions can mediate autophagy, which has attracted increasing attention.…”

Section: Extracellular Vesiclesmentioning

confidence: 99%

The Role of Autophagy in Hypoxia-Induced Neuroinflammation

Sha

Tan

Miao

et al. 2021

DNA and Cell Biology

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Autophagy is a critical cytoprotective mechanism that takes a hand in innate or adaptive immune responses. Hypoxia is a common pathophysiological mechanism that can lead to systemic pathological reactions. In recent years, the impact of hypoxia on the central nervous system has attracted more attention. In the past, autophagy was thought to be directly involved in the apoptosis of nerve cells under hypoxia. An increasing amount of evidence shows that the neuroinflammatory response plays an indispensable role in the neural damage caused by hypoxia. There are many mechanisms related to the neuroinflammatory response induced by hypoxia, among which autophagy is an important aspect, but the role of autophagy is still unclear. This article focuses on how autophagy flux of central immune cells is modified under hypoxic conditions, and how this autophagy affects neuroinflammatory response.

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Brain-derived microparticles activate microglia/macrophages and induce neuroinflammation

Cited by 24 publications

References 21 publications

<p>Atorvastatin Combined with Low-Dose Dexamethasone Treatment Protects Endothelial Function Impaired by Chronic Subdural Hematoma via the Transcription Factor KLF-2</p>

<p>Atorvastatin Combined with Low-Dose Dexamethasone Treatment Protects Endothelial Function Impaired by Chronic Subdural Hematoma via the Transcription Factor KLF-2</p>

Brain-Derived Microparticles (BDMPs) Contribute to Neuroinflammation and Lactadherin Reduces BDMP Induced Neuroinflammation and Improves Outcome After Stroke

The Role of Autophagy in Hypoxia-Induced Neuroinflammation

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