scholarly journals Hepatic Small Extracellular Vesicles Promote Microvascular Endothelial Hyperpermeability During NAFLD via novel-miRNA-7

2021 ◽  
Author(s):  
Rui Zuo ◽  
Li-feng Ye ◽  
Yi Huang ◽  
Zi-qing Song ◽  
Lei Wang ◽  
...  
Keyword(s):  
Extracellular Vesicles ◽  
Nlrp3 Inflammasome ◽  
Cathepsin B ◽  
Microvascular Complications ◽  
Endothelial Barrier ◽  
Coronary Microvascular Dysfunction ◽  
Inflammasome Activation ◽  
Barrier Dysfunction ◽  
Microvascular Endothelial ◽  
Endothelial Hyperpermeability

Abstract BackgroundA recent study has reported that patients with nonalcoholic fatty liver disease (NAFLD) are more susceptible to coronary microvascular dysfunction (CMD), which may predict major adverse cardiac events. However, little is known regarding the causes of CMD during NAFLD. In this study, we aimed to explore the role of hepatic small extracellular vesicles (sEVs) in regulating the endothelial dysfunction of coronary microvessels during NAFLD.ResultsWe established two murine NAFLD models by feeding mice a methionine-choline-deficient (MCD) diet for 4 weeks or a high-fat diet (HFD) for 16 weeks. We found that the NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome-dependent endothelial hyperpermeability occurred in coronary microvessels during both MCD diet and HFD-induced NAFLD. The in vivo and in vitro experiments proved that novel-miR-7-abundant hepatic sEVs were responsible for NLRP3 inflammasome-dependent endothelial barrier dysfunction. Mechanistically, novel-miR-7 directly targeted lysosomal associated membrane protein 1 (LAMP1) and promotes lysosomal membrane permeability (LMP), which in turn induced Cathepsin B-dependent NLRP3 inflammasome activation and microvascular endothelial hyperpermeability. Conversely, a specific novel-miR-7 inhibitor markedly improved endothelial barrier integrity. Finally, we proved that steatotic hepatocyte was a main resource of novel-miR-7-contained hepatic sEVs, and steatotic hepatocyte-derived sEVs were able to promote NLRP3 inflammasome-dependent microvascular endothelial hyperpermeability through novel-miR-7.ConclusionsHepatic sEVs contribute to endothelial hyperpermeability in coronary microvessels by delivering novel-miR-7 and targeting the LAMP1/Cathepsin B/NLRP3 inflammasome axis during NAFLD. Our study brings new insights into the liver-to-microvessel cross-talk and may provide a new diagnostic biomarker and treatment target for microvascular complications of NAFLD.

scholarly journals Hepatic small extracellular vesicles promote microvascular endothelial hyperpermeability during NAFLD via novel-miRNA-7

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Rui Zuo ◽  
Li-Feng Ye ◽  
Yi Huang ◽  
Zi-Qing Song ◽  
Lei Wang ◽  
...  
Keyword(s):  
Extracellular Vesicles ◽  
Nlrp3 Inflammasome ◽  
Cathepsin B ◽  
Microvascular Complications ◽  
Endothelial Barrier ◽  
Coronary Microvascular Dysfunction ◽  
Inflammasome Activation ◽  
Barrier Dysfunction ◽  
Microvascular Endothelial ◽  
Endothelial Hyperpermeability

Abstract Background A recent study has reported that patients with nonalcoholic fatty liver disease (NAFLD) are more susceptible to coronary microvascular dysfunction (CMD), which may predict major adverse cardiac events. However, little is known regarding the causes of CMD during NAFLD. In this study, we aimed to explore the role of hepatic small extracellular vesicles (sEVs) in regulating the endothelial dysfunction of coronary microvessels during NAFLD. Results We established two murine NAFLD models by feeding mice a methionine-choline-deficient (MCD) diet for 4 weeks or a high-fat diet (HFD) for 16 weeks. We found that the NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome-dependent endothelial hyperpermeability occurred in coronary microvessels during both MCD diet and HFD-induced NAFLD. The in vivo and in vitro experiments proved that novel-microRNA(miR)-7-abundant hepatic sEVs were responsible for NLRP3 inflammasome-dependent endothelial barrier dysfunction. Mechanistically, novel-miR-7 directly targeted lysosomal associated membrane protein 1 (LAMP1) and promotes lysosomal membrane permeability (LMP), which in turn induced Cathepsin B-dependent NLRP3 inflammasome activation and microvascular endothelial hyperpermeability. Conversely, a specific novel-miR-7 inhibitor markedly improved endothelial barrier integrity. Finally, we proved that steatotic hepatocyte was a significant source of novel-miR-7-contained hepatic sEVs, and steatotic hepatocyte-derived sEVs were able to promote NLRP3 inflammasome-dependent microvascular endothelial hyperpermeability through novel-miR-7. Conclusions Hepatic sEVs contribute to endothelial hyperpermeability in coronary microvessels by delivering novel-miR-7 and targeting the LAMP1/Cathepsin B/NLRP3 inflammasome axis during NAFLD. Our study brings new insights into the liver-to-microvessel cross-talk and may provide a new diagnostic biomarker and treatment target for microvascular complications of NAFLD. Graphical Abstract

scholarly journals Oxidative Stress is the Principal Contributor to Inflammasome Activation in Retinal Pigment Epithelium Cells with Defunct Proteasomes and Autophagy

2018 ◽  
Vol 49 (1) ◽  
pp. 359-367 ◽  
Author(s):  
Niina Piippo ◽  
Eveliina Korhonen ◽  
Maria Hytti ◽  
Kati Kinnunen ◽  
Kai Kaarniranta ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Nlrp3 Inflammasome ◽  
Cathepsin B ◽  
Retinal Pigment ◽  
Inflammasome Activation ◽  
Bafilomycin A1 ◽  
Potassium Efflux ◽  
Rpe Cells ◽  
Activation Mechanisms ◽  
And Oxidative Stress

Background/Aims: Previously, we demonstrated that blockade of the intracellular clearance systems in human retinal pigment epithelial (RPE) cells by MG-132 and bafilomycin A1 (BafA) induces NLRP3 inflammasome signaling. Here, we have explored the activation mechanisms behind this process. NLRP3 is an intracellular receptor detecting factors ranging from the endogenous alarmins and adenosine triphosphate (ATP) to ultraviolet radiation and solid particles. Due to the plethora of triggers, the activation of NLRP3 is often indirect and can be mediated through several alternative pathways. Potassium efflux, lysosomal rupture, and oxidative stress are currently the main mechanisms associated with many activators. Methods: NLRP3 inflammasomes were activated in human RPE cells by blocking proteasomes and autophagy using MG-132 and bafilomycin A1 (BafA), respectively. P2X7 inhibitor A740003, potassium chloride (KCl), and glyburide, or N-acetyl-L-cysteine (NAC), ammonium pyrrolidinedithiocarbamate (APDC), diphenyleneiodonium chloride (DPI), and mito-TEMPO were added to cell cultures in order to study the role of potassium efflux and oxidative stress, respectively. IL-1β was measured using the ELISA method. ATP levels and cathepsin B activity were examined using commercial kits, and ROS levels using the fluorescent dye 2´,7´-dichlorodihydrofluorescein diacetate (DCFDA). Results: Elevated extracellular potassium prevented the priming factor IL-1α from inducing the production of reactive oxygen species (ROS). It also prevented IL-1β release after exposure of primed cells to MG-132 and BafA. Inflammasome activation increased extracellular ATP levels, which did not appear to trigger significant potassium efflux. The activity of the lysosomal enzyme, cathepsin B, was reduced by MG-132 and BafA, suggesting that cathepsin B was not playing any role in this phenomenon. Instead, MG-132 triggered ROS production already 30 min after exposure, but treatment with antioxidants blocking NADPH oxidase and mitochondria-derived ROS significantly prevented IL-1β release after this activating signal. Conclusion: Our data suggest that oxidative stress strongly contributes to the NLRP3 inflammasome activation upon dysfunctional cellular clearance. Clarification of inflammasome activation mechanisms provides novel options for alleviating pathological inflammation present in aggregation diseases, such as age-related macular disease (AMD) and Alzheimer’s disease.

scholarly journals Maternal extracellular vesicles and platelets promote preeclampsia via inflammasome activation in trophoblasts

Blood ◽  
2016 ◽  
Vol 128 (17) ◽  
pp. 2153-2164 ◽  
Author(s):  
Shrey Kohli ◽  
Satish Ranjan ◽  
Juliane Hoffmann ◽  
Muhammed Kashif ◽  
Evelyn A. Daniel ◽  
...  
Keyword(s):  
Extracellular Vesicles ◽  
Nlrp3 Inflammasome ◽  
Purinergic Signaling ◽  
Atp Release ◽  
Inflammasome Activation ◽  
Trophoblast Cells ◽  
Nlrp3 Inflammasome Activation ◽  
Key Points

Key Points EVs cause accumulation of activated maternal platelets within the placenta, resulting in a thromboinflammatory response and PE. Activated maternal platelets cause NLRP3-inflammasome activation in trophoblast cells via ATP release and purinergic signaling.

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