A20 protects neuronal apoptosis stimulated by lipopolysaccharide-induced microglial exosomes

Chen, Xiaoqing; Qian, Boyu; Kong, Xin Ying; Hao, Jie; Ye, Yong; Yang, Kai Chiang; Xu, Tianli; Zhang, Feng

doi:10.1016/j.neulet.2019.134480

Cited by 17 publications

(10 citation statements)

References 38 publications

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“…To confirm that the particles in the exosomal fraction were indeed exosomes, we assessed whether they displayed common exosomal characteristics. Classical exosomal markers, such as CD63, CD9, ALIX, CD81, HSP70, TSG101 and Flotillin-1 ( Hooper et al , 2012 ; Witwer et al , 2013 ; Fröhlich et al ., 2014 ; Mehdiani et al , 2015 ; Schiera et al , 2015 ; Horibe et al , 2018 ; Chen et al , 2019 ) were all found to be expressed in the iPS-Mg exosomal fraction of both Cv and R47H het derived exosomes ( Fig. 1A and Supplementary Fig.…”

Section: Resultsmentioning

confidence: 94%

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The influence of the R47H triggering receptor expressed on myeloid cells 2 variant on microglial exosome profiles

Mallach

Gobom

Zetterberg

et al. 2021

Brain Communications

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Variants in the triggering receptor expressed on myeloid cells 2 (TREM2) gene are linked with an increased risk of dementia, in particular the R47Hhet TREM2 variant is linked to late-onset Alzheimer’s disease. Using human iPSC-derived microglia, we assessed whether variations in the dynamics of exosome secretion, including their components, from these cells might underlie some of this risk. We found exosome size was not altered between common variant controls and R47Hhet variants, but the amount and constitution of exosomes secreted were different. Exosome quantities were rescued by incubation with an ATP donor or with lipids via a phosphatidylserine TREM2 ligand. Following a lipopolysaccharide or phagocytic cell stimulus, exosomes from common variant and R47Hhet microglia were found to contain cytokines, chemokines, APOE and TREM2. Differences were observed in the expression of CCL22, IL-1β and TREM2 between common variant and R47Hhet derived exosomes. Furthermore unlike common variant-derived exosomes, R47Hhet exosomes contained additional proteins linked to negative regulation of transcription and metabolic processes. Subsequent addition of exosomes to stressed neurones showed R47Hhet-derived exosomes to be less protective. These data have ramifications for the responses of microglia in Alzheimer’s disease and may point to further targets for therapeutic intervention.

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Section: Resultsmentioning

confidence: 94%

“…As microglia exosomes have been shown to affect neuronal functioning ( Antonucci et al , 2012 ; Chen et al , 2019 ) we determined whether iPS-Mg-derived exosomes from Cv or R47H het cells were taken up into neurons ( Fig. 7 ).…”

Section: Resultsmentioning

confidence: 99%

The influence of the R47H triggering receptor expressed on myeloid cells 2 variant on microglial exosome profiles

Mallach

Gobom

Zetterberg

et al. 2021

Brain Communications

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“…To examine the effect of LPS treatment on human cardiomyocytes, AC16 cells were treated with increasing concentrations of LPS, which represent varying levels of bacterial infection [18][19][20]. Cell viability was measured after 48 h of LPS treatment.…”

Section: Viability Of Cardiomyocytes After Lps Treatmentmentioning

confidence: 99%

“…For control cells, exosome-free DMEM/F-12 only was used. The cells Biology 2019, 8, 69 3 of 10 and LPS were incubated for 48 hours (h) without any further manipulation [18][19][20]. The culture media was collected after 48 h.…”

mentioning

confidence: 99%

The Role of Lipopolysaccharide-Induced Extracellular Vesicles in Cardiac Cell Death

Bell

Jones

Crenshaw

et al. 2019

Biology

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Exosomes play a crucial role in the progression of infectious diseases, as exosome release and biogenesis are affected by external factors, such as pathogenic infections. Pyrogens may aide in the progression of diseases by triggering inflammation, endothelial cell injury, and arterial plaque rupture, all of which can lead to acute coronary disease, resulting in cardiac tissue death and the onset of a cardiac event (CE). To better understand the effects of Gram-negative bacterial infections on exosome composition and biogenesis, we examined exosome characteristics after treatment of AC16 human cardiomyocytes with lipopolysaccharide (LPS), which served as a model system for Gram-negative bacterial infection. Using increasing doses (0, 0.1, 1, or 10 µg) of LPS, we showed that treatment with LPS substantially altered the composition of AC16-derived exosomes. Both the relative size and the quantity (particles/mL) of exosomes were decreased significantly at all tested concentrations of LPS treatment compared to the untreated group. In addition, LPS administration reduced the expression of exosomal proteins that are related to exosomal biogenesis. Conversely, we observed an increase in immunomodulators present after LPS administration. This evaluation of the impact of LPS on cardiac cell death and exosome composition will yield new insight into the importance of exosomes in a variety of physiological and pathological processes as it relates to disease progression, diagnosis, and treatment.

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“…KO of A20 in PC1 cells promotes the apoptotic response to exosomes from microglial cells. This suggests that A20 exhibits anti-apoptotic functions in a brain injury model [ 141 ]. In TRAIL/RIPK1-mediated apoptosis, A20 suppresses apoptosis by ubiquitinating RIPK1 with a K63-linked ubiquitin chain at which caspase-8 is recruited and inhibited [ 142 ].…”

Section: Dubs Regulating Diverse Rcdmentioning

confidence: 99%

Deubiquitinases: Modulators of Different Types of Regulated Cell Death

Lee

Kim

Hwang

et al. 2021

IJMS

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The mechanisms and physiological implications of regulated cell death (RCD) have been extensively studied. Among the regulatory mechanisms of RCD, ubiquitination and deubiquitination enable post-translational regulation of signaling by modulating substrate degradation and signal transduction. Deubiquitinases (DUBs) are involved in diverse molecular pathways of RCD. Some DUBs modulate multiple modalities of RCD by regulating various substrates and are powerful regulators of cell fate. However, the therapeutic targeting of DUB is limited, as the physiological consequences of modulating DUBs cannot be predicted. In this review, the mechanisms of DUBs that regulate multiple types of RCD are summarized. This comprehensive summary aims to improve our understanding of the complex DUB/RCD regulatory axis comprising various molecular mechanisms for diverse physiological processes. Additionally, this review will enable the understanding of the advantages of therapeutic targeting of DUBs and developing strategies to overcome the side effects associated with the therapeutic applications of DUB modulators.

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A20 protects neuronal apoptosis stimulated by lipopolysaccharide-induced microglial exosomes

Cited by 17 publications

References 38 publications

The influence of the R47H triggering receptor expressed on myeloid cells 2 variant on microglial exosome profiles

The influence of the R47H triggering receptor expressed on myeloid cells 2 variant on microglial exosome profiles

The Role of Lipopolysaccharide-Induced Extracellular Vesicles in Cardiac Cell Death

Deubiquitinases: Modulators of Different Types of Regulated Cell Death

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