scholarly journals LPS-induced macrophage HMGB1-loaded extracellular vesicles trigger hepatocyte pyroptosis by activating the NLRP3 inflammasome

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Guozhen Wang ◽  
Siyi Jin ◽  
Weichang Huang ◽  
Yang Li ◽  
Jun Wang ◽  
...  
Keyword(s):  
Cell Death ◽  
Extracellular Vesicles ◽  
Tissue Injury ◽  
High Mobility ◽  
Extracellular Vesicle ◽  
Target Cells ◽  
Hmgb1 Level ◽  
Pyrin Domain ◽  
Molecular Pattern ◽  
Liver Injuries

AbstractExtracellular vesicles (EVs) have emerged as important vectors of intercellular dialogue. High mobility group box protein 1 (HMGB1) is a typical damage-associated molecular pattern (DAMP) molecule, which is cytotoxic and leads to cell death and tissue injury. Whether EVs are involved in the release of HMGB1 in lipopolysaccharide (LPS)-induced acute liver injuries need more investigation. EVs were identified by transmission electron microscopy, nanoparticle tracking analysis (NTA), and western blotting. The co-localization of HMGB1, RAGE (receptor for advanced glycation end-products), EEA1, Rab5, Rab7, Lamp1 and transferrin were detected by confocal microscopy. The interaction of HMGB1 and RAGE were investigated by co-immunoprecipitation. EVs were labeled with the PKH67 and used for uptake experiments. The pyroptotic cell death was determined by FLICA 660-YVAD-FMK. The expression of NLRP3 (NOD-like receptor family pyrin domain containing 3) inflammasomes were analyzed by western-blot or immunohistochemistry. Serum HMGB1, ALT (alanine aminotransferase), AST (aspartate aminotransferase), LDH (lactate dehydrogenase) and MPO (myeloperoxidase) were measured using a commercial kit. The extracellular vesicle HMGB1 was detected in the serums of sepsis patients. Macrophages were found to contribute to HMGB1 release through the EVs. HMGB1-RAGE interactions participated in the loading of HMGB1 into the EVs. These EVs shuttled HMGB1 to target cells by transferrin-mediated endocytosis leading to hepatocyte pyroptosis by the activation of NLRP3 inflammasomes. Moreover, a positive correlation was verified between the sepsis serum EVs-HMGB1 level and clinical liver damage. This finding provides insights for the development of novel diagnostic and therapeutic strategies for acute liver injuries.

scholarly journals Stoking the Fire: How Dying Cells Propagate Inflammatory Signalling through Extracellular Vesicle Trafficking

2020 ◽  
Vol 21 (19) ◽  
pp. 7256
Author(s):  
Amy A. Baxter
Keyword(s):  
Cell Death ◽  
Extracellular Vesicles ◽  
Tissue Injury ◽  
Extracellular Vesicle ◽  
Bioactive Molecules ◽  
Target Cells ◽  
Acute Tissue Injury ◽  
Cellular Turnover ◽  
Unique Cell ◽  
Dying Cells

Communication between dying cells and their environment is a critical process that promotes tissue homeostasis during normal cellular turnover, whilst during disease settings, it can contribute to inflammation through the release of intracellular factors. Extracellular vesicles (EVs) are a heterogeneous class of membrane-bound cell-derived structures that can engage in intercellular communication via the trafficking of bioactive molecules between cells and tissues. In addition to the well-described functions of EVs derived from living cells, the ability of dying cells to release EVs capable of mediating functions on target cells or tissues is also of significant interest. In particular, during inflammatory settings such as acute tissue injury, infection and autoimmunity, the EV-mediated transfer of proinflammatory cargo from dying cells is an important process that can elicit profound proinflammatory effects in recipient cells and tissues. Furthermore, the biogenesis of EVs via unique cell-death-associated pathways has also been recently described, highlighting an emerging niche in EV biology. This review outlines the mechanisms and functions of dying-cell-derived EVs and their ability to drive inflammation during various modes of cell death, whilst reflecting on the challenges and knowledge gaps in investigating this subgenre of extracellular vesicles research.

The Role of High Mobility Group Box 1 (HMGB1) in Neurodegeneration: A Systematic Review

2022 ◽  
Vol 20 ◽  
Author(s):  
Fathimath Zaha Ikram ◽  
Alina Arulsamy ◽  
Thaarvena Retinasamy ◽  
Mohd. Farooq Shaikh
Keyword(s):  
Systematic Review ◽  
Tissue Injury ◽  
High Mobility ◽  
High Mobility Group ◽  
Hmgb1 Protein ◽  
Toll Like Receptor 4 ◽  
Neuroinflammatory Response ◽  
Molecular Pattern ◽  
Glycation End Products

Background: High mobility group box 1 (HMGB1) protein is a damage-associated molecular pattern (DAMP) molecule that plays an important role in the repair and regeneration of tissue injury. It also acts as a pro-inflammatory cytokine through the activation of toll-like receptor 4 (TLR4) and receptor for advanced glycation end products (RAGE), to elicit the neuroinflammatory response. HMGB1 may aggravate several cellular responses which may lead to pathological inflammation and cellular death. Thus, there have been a considerable amount of research into the pathological role of HMGB1 in diseases. However, whether the mechanism of action of HMGB1 is similar in all neurodegenerative disease pathology remains to be determined. Objective: Therefore, this systematic review aimed to critically evaluate and elucidate the role of HMGB1 in the pathology of neurodegeneration based on the available literature. Methods: A comprehensive literature search was performed on four databases; EMBASE, PubMed, Scopus, and CINAHL Plus. Results: A total of 85 articles were selected for critical appraisal, after subjecting to the inclusion and exclusion criteria in this study. The selected articles revealed that HMGB1 levels were found elevated in most neurodegeneration except in Huntington’s disease and Spinocerebellar ataxia, where the levels were found decreased. This review also showcased that HMGB1 may act on distinctive pathways to elicit its pathological response leading to the various neurodegeneration processes/diseases. Conclusion: While there have been promising findings in HMGB1 intervention research, further studies may still be required before any HMGB1 intervention may be recommended as a therapeutic target for neurodegenerative diseases.

Dynamic Defense System Against HMGB1, a Proinflammatory and Lethal Mediator in Severe Infections and Malignancies.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3827-3827
Author(s):  
Takashi Ito ◽  
Kazuhiro Abeyama ◽  
Ko-ichi Kawahara ◽  
Kamal K. Biswas ◽  
Tomonori Uchimura ◽  
...  
Keyword(s):  
Tissue Injury ◽  
High Mobility ◽  
Inflammatory Cells ◽  
Defense System ◽  
Hmgb1 Level ◽  
Beneficial Effects ◽  
Extracellular Milieu ◽  
Severe Infections ◽  
Serum Hmgb1 Level ◽  
Severe Tissue

Abstract High Mobility Group box 1(HMGB1) is an abundant DNA-binding protein that acts as a proinflammatory cytokine when released in the extracellular milieu by necrotic and inflammatory cells. Moreover, an increased HMGB1 in the circulation of septic patients may induce multi-organ failure and lethality. However, very recent observations suggest that the protein also acts as an innate adjuvant, stem cell chemoattractant and growth factor. Thus only systemic and circulatory HMGB1 may induce morbidity and mortality, however, localized HMGB1 may have beneficial effects. Therefore, we serially examined the serum HMGB1 level in patients with various diseases, and also evaluated the significance of the protein. We demonstrate here how HMGB1 is localized and acts as an immune-adjuvant and a repairing factor in damaged tissue. We first established specific ELISA method to measure HMGB1. An increased level of HMGB1 was detected in the serum from patients with sever sepsis, infections, malignancy and so on. However, serum HMGB1 concentrations were fluctuated during the clinical course, and could not be concluded as a lethal mediator as previously reported. Next we investigated the reason of dynamic fluctuations of the protein in the circulation. Based on our findings, we proposed that this fluctuation of HMGB1 concentrations may be mediated by at least following three fashions; 1) proteolytic degradation by plasmin and thrombin, 2) endothelial thrombomodulin(TM) adsorption, and 3) generation of antibody against the protein. We observed that plasmin efficiently degraded HMGB1 into small fragments. However, interestingly the generated fragments of the protein still possess an ability to produce TNFa in macrophages through an undefined pathway. TM binds the protein on its N-terminus lectin-like domain. Binding of HMGB1 to TM resulted in decrement of TM’s cofactor activity to activate protein C by thrombin. HMGB1 bound to TM was gradually degraded by thrombin. These may be a system to localize HMGB1 only in injury sites where TM is down-regulated or disappeared through endothelial-loss. This may exert endothelial defense system against extracellular HMGB1 in severe tissue injury. Another possibility is that the generated antibody against HMGB1 may neutralize the proinflammatory action of the protein. In this context, we found that some of the antibodies against HMGB1 have the characteristics of P-ANCA(perinuclear anti-neutrophil cytoplasmic antibody). This may alter the phenotype of the underlining diseases. In conclusion, we suggest that HMGB1 is not merely a lethal mediator, but a kind of “testament” mediator of cell necrosis or invasive attacks to dendritic cells.

scholarly journals Neurons Are a Primary Driver of Inflammation Via Release of HMGB1

Cells ◽  
2021 ◽  
Vol 10 (10) ◽  
pp. 2791
Author(s):  
Huan Yang ◽  
Ulf Andersson ◽  
Michael Brines
Keyword(s):  
Molecular Markers ◽  
Tissue Injury ◽  
Inflammatory Diseases ◽  
High Mobility ◽  
Sensory Nerves ◽  
Knock Out ◽  
Etiologic Role ◽  
Molecular Pattern ◽  
Primary Driver ◽  
Direct Targeting

Recent data show that activation of nociceptive (sensory) nerves turns on localized inflammation within the innervated area in a retrograde manner (antidromically), even in the absence of tissue injury or molecular markers of foreign invaders. This neuroinflammatory process is activated and sustained by the release of neuronal products, such as neuropeptides, with the subsequent amplification via recruitment of immunocompetent cells, including macrophages and lymphocytes. High mobility group box 1 protein (HMGB1) is a highly conserved, well characterized damage-associated molecular pattern molecule expressed by many cells, including nociceptors and is a marker of inflammatory diseases. In this review, we summarize recent evidence showing that neuronal HMGB1 is required for the development of neuroinflammation, as knock out limited to neurons or its neutralization via antibodies ameliorate injury in models of nerve injury and of arthritis. Further, the results of study show that HMGB1 is actively released during neuronal depolarization and thus plays a previously unrecognized key etiologic role in the initiation and amplification of neuroinflammation. Direct targeting of HMGB1 is a promising approach for novel anti-inflammatory therapy.

scholarly journals Autophagy Regulates the Effects of Adipose-Derived Stem Cell Small Extracellular Vesicles On Lipopolysaccharide-Induced Pulmonary Microvascular Barrier Damage

2022 ◽  
Author(s):  
Chichi Li ◽  
Min Wang ◽  
Wangjia Wang ◽  
Yuping Li ◽  
Dan Zhang
Keyword(s):  
Stem Cell ◽  
Acute Lung Injury ◽  
Lung Injury ◽  
Extracellular Vesicles ◽  
Tissue Injury ◽  
Stem Cell Differentiation ◽  
Microvascular Endothelial Cell ◽  
Target Cells ◽  
Autophagy Inhibition

Abstract Background: Small extracellular vesicles (sEVs) have been recognized to be more effective than direct stem cell differentiation into functional target cells in preventing tissue injury and promoting tissue repair. Our previous study demonstrated the protective effect of adipose-derived stem cells (ADSCs) on lipopolysaccharide (LPS)-induced acute lung injury and the effect of autophagy on ADSC functions, but the role of ADSC-derived sEVs (ADSC-sEVs) and autophagy-mediated regulation of ADSC-sEVs in LPS-induced pulmonary microvascular barrier damage remains unclear. Methods: After treatment with sEVs from ADSCs with or without autophagy inhibition, LPS-induced human pulmonary microvascular endothelial cell (HPMVECs) barrier damage was detected. LPS-induced acute lung injury in mice was assessed in vivo after intravenous administration of sEVs from ADSCs with or without autophagy inhibition. The effects of autophagy on the bioactive miRNA components of ADSC-sEVs were assessed after prior inhibition of cell autophagy. Results: We found that ADSC-sEV effectively alleviated LPS-induced apoptosis, tight junction damage and high permeability of PMVECs. Moreover, in vivo administration of ADSC-sEV markedly inhibited LPS-triggered lung injury. However, autophagy inhibition, markedly weakened the therapeutic effect of ADSC-sEVs on LPS-induced PMVECs barrier damage and acute lung injury. In addition, autophagy inhibition, prohibited the expression of five specific miRNAs in ADSC-sEVs -under LPS-induced inflammatory conditions. Conclusions: Our results indicate that ADSC-sEVs protect against LPS-induced pulmonary microvascular barrier damage and acute lung injury. Autophagy is a positive mediator of sEVs function, at least in part through controlling the expression of bioactive miRNAs in sEVs.

scholarly journals Extracellular Vesicles: A Novel Opportunity for Precision Medicine in Respiratory Diseases

2021 ◽  
Vol 8 ◽  
Author(s):  
Jonathan M. Carnino ◽  
Zhi Hao Kwok ◽  
Yang Jin
Keyword(s):  
Precision Medicine ◽  
Extracellular Vesicles ◽  
Biological Fluids ◽  
Relative Size ◽  
Extracellular Vesicle ◽  
The Body ◽  
Size Exclusion ◽  
Physiological Status ◽  
Target Cells

Extracellular vesicles are membrane-bound nanoparticles secreted by cells which play a well-known role in cell to cell communication. The most update to date nomenclature categorizes extracellular vesicles based on their relative size, protein markers, and/or the cell type of origin. Extracellular vesicles can be isolated from biological fluids using a variety of methods, including but not limited to, ultrafiltration, size-exclusion chromatography, differential ultracentrifugation, density gradient centrifugation, precipitation-based methods, and immunoaffinity capture. These nanovesicles carry distinct “cargo,” made up of biomolecules such as nucleic acids, lipids, and protein, which is delivered to nearby target cells. The “cargo” profile carried by extracellular vesicles is critical in their role of communication and resembles the physiological status of the cell they originated from. For the purpose of this review, we will focus on the miRNA cargo. Extracellular vesicle-miRNA profiles hold the potential to be used in diagnostic panels for a variety of diseases through a novel method known as “liquid biopsy.” In addition to this, extracellular vesicles may serve as a potential method to deliver drugs to specific cells within the body. This mini-review provides background into what extracellular vesicles are, methods of isolating these nanoparticles, their potential use as a biomarker and drug delivery system for precision medicine, and a summary of the current literature covering the role of some extracellular vesicle-cargo's in various pulmonary diseases.

scholarly journals Visualizing murine placental extracellular vesicle data with tidyNano: a computational framework for analyzing and visualizing nanoparticle data in R

2018 ◽  
Author(s):  
Sean L Nguyen ◽  
Jacob W Greenberg ◽  
Hao Wang ◽  
Benjamin W Collaer ◽  
Jianrong Wang ◽  
...  
Keyword(s):  
Extracellular Vesicles ◽  
Web Application ◽  
R Package ◽  
Extracellular Vesicle ◽  
Target Cells ◽  
Computational Framework ◽  
Particle Count ◽  
Efficient Calculation ◽  
Fluid Concentration ◽  
Conventional Microscopy

AbstractExtracellular vesicles (EVs) are increasingly recognized as important mediators of intercellular communication, and in mammals are generally classified as ~50–150nm exosomes, ~100–1000nm microvesicles, and apoptotic bodies, each arising as a result of different biological processes. EVs carry protein, lipids, and nucleic acids within the circulation, to target cells whereupon they mediate physiological changes. Due to their small size, quantification and characterization by conventional microscopy is not possible. However, nanoparticle tracking analysis (NTA) has provided a method to determine the fluid concentration and size of extracellular vesicles and other nanoparticles. While NTA provides statistical summaries of samples in an experiment, a recurring difficulty is the organization, manipulation, and management of raw particle count data because of the large size of datasets, and resultant vulnerability to user error. To address these limitations, we developed tidyNano, an R package that provides functions to import, clean, and quickly summarize raw NanoSight (Malvern Panalytical) data for efficient calculation of statistics and visualization. Here, we provide a framework for importing raw nanoparticle data and provide functions to facilitate rapid and efficient analysis, visualization and calculation of summary statistics. tidyNano was used to analyze murine plasma extracellular vesicles across gestation by aggregating and summarizing samples based on technical, biological and gestational parameters. In addition, we developed shinySIGHT, a Shiny web application that allows for interactive exploration and visualization of EV data. Using this package, we analyzed data generated from 36 samples of EV derived from the plasma of mice across gestation.Peripheral EV concentration increased linearly across pregnancy, with trending increases as early as gestation day (GD) 5.5 and significant rises at GD14.5, and 17.5 relative to EV concentrations in nonpregnant females. Thus, the data highlight the utility of the mouse as a model of EV biology in pregnancy. Further, the package provides a mechanism for seamless analysis of EV data generated by NanoSight. Importantly, this package provides a straightforward framework by which diverse types of large datasets can be simply and efficiently analyzed. tidyNano and shinySIGHT are freely available under the MIT license and is hosted on GitHub (https://nguyens7.github.io/tidyNano/).

scholarly journals Myocardial infarction affects Cx43 content of extracellular vesicles secreted by cardiomyocytes

2020 ◽  
Vol 3 (12) ◽  
pp. e202000821
Author(s):  
Tania Martins-Marques ◽  
Teresa Ribeiro-Rodrigues ◽  
Saskia C de Jager ◽  
Monica Zuzarte ◽  
Cátia Ferreira ◽  
...  
Keyword(s):  
Extracellular Vesicles ◽  
Intercellular Communication ◽  
Connexin 43 ◽  
Extracellular Vesicle ◽  
Therapeutic Strategies ◽  
Target Cells ◽  
Comprehensive Strategy ◽  
Junction Protein ◽  
Gap Junction Protein

Ischemic heart disease has been associated with an impairment on intercellular communication mediated by both gap junctions and extracellular vesicles. We have previously shown that connexin 43 (Cx43), the main ventricular gap junction protein, assembles into channels at the extracellular vesicle surface, mediating the release of vesicle content into target cells. Here, using a comprehensive strategy that included cell-based approaches, animal models and human patients, we demonstrate that myocardial ischemia impairs the secretion of Cx43 into circulating, intracardiac and cardiomyocyte-derived vesicles. In addition, we show that ubiquitin signals Cx43 release in basal conditions but appears to be dispensable during ischemia, suggesting an interplay between ischemia-induced Cx43 degradation and secretion. Overall, this study constitutes a step forward for the characterization of the signals and molecular players underlying vesicle protein sorting, with strong implications on long-range intercellular communication, paving the way towards the development of innovative diagnostic and therapeutic strategies for cardiovascular disorders.

scholarly journals Roles of High Mobility Group Box 1 in Cardiovascular Calcification

2017 ◽  
Vol 42 (2) ◽  
pp. 427-440 ◽  
Author(s):  
Qiang Chen ◽  
Ze-Yang Wang ◽  
Li-Yuan Chen ◽  
Hou-Yuan Hu
Keyword(s):  
Cell Activation ◽  
High Mobility ◽  
Extracellular Vesicle ◽  
High Mobility Group ◽  
Ectopic Calcification ◽  
Cardiac Events ◽  
Calcific Aortic Valve Disease ◽  
Molecular Pattern ◽  
Underlying Mechanisms ◽  
Almost All

Calcific disease of the cardiovascular system, including atherosclerotic calcification, medial calcification in diabetes and calcific aortic valve disease, is an important risk factor for many adverse cardiovascular events such as ischemic cardiac events and subsequent mortality. Although cardiovascular calcification has long been considered to be a passive degenerative occurrence, it is now recognized as an active and highly regulated process that involves osteochondrogenic differentiation, apoptosis and extracellular vesicle release. Nonetheless, despite numerous studies on the pathogenesis of cardiovascular calcification, the underlying mechanisms remain poorly understood. High mobility group box 1 (HMGB1), a nuclear protein bound to chromatin in almost all eukaryotic cells, acts as a damage-associated molecular pattern (DAMP) when released into the extracellular space upon cell activation, injury or death. Moreover, HMGB1 also functions as a bone-active cytokine participating in bone remodeling and ectopic calcification pathogenesis. However, studies on the roles of HMGB1 in promoting cardiovascular calcification are limited to date, and the mechanisms involved are still unclear. In this review, we summarize recent studies investigating the mechanism of cardiovascular calcification and discuss multiple roles of HMGB1 in its development.

scholarly journals Communicating with the dead: lipids, lipid mediators and extracellular vesicles

2018 ◽  
Vol 46 (3) ◽  
pp. 631-639 ◽  
Author(s):  
Andrew Devitt ◽  
Helen R. Griffiths ◽  
Ivana Milic
Keyword(s):  
Cell Death ◽  
Extracellular Vesicles ◽  
Apoptotic Cell ◽  
Cell Communication ◽  
Extracellular Vesicle ◽  
Lipid Mediators ◽  
Effective Control ◽  
The Dead ◽  
Dying Cells

Apoptosis is a key event in the control of inflammation. However, for this to be successful, dying cells must efficiently and effectively communicate their presence to phagocytes to ensure timely removal of dying cells. Here, we consider apoptotic cell-derived extracellular vesicles and the role of contained lipids and lipid mediators in ensuring effective control of inflammation. We discuss key outstanding issues in the study of cell death and cell communication, and introduce the concept of the ‘active extracellular vesicle’ as a metabolically active and potentially changing intercellular communicator.

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