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

Baxter, Amy A.

doi:10.3390/ijms21197256

Cited by 14 publications

(15 citation statements)

References 107 publications

(141 reference statements)

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“…Necrotic cells release a large amount of DAMPs and PS-positive microparticles that amplify local and disseminated coagulation and inflammation (Fig. 5) (15,101). Finally, EC death involves loss of structural and membrane properties, which aggravates the sepsis-and ROS-induced permeability, the capillary protein and fluids leakage, and therefore organ injury (61).…”

Section: Os-induced Ec Deathmentioning

confidence: 99%

Oxidative Stress and Endothelial Dysfunction in Sepsis and Acute Inflammation

Joffre

Hellman

2021

Antioxidants & Redox Signaling

144

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Significance: Under homeostatic conditions, the endothelium dynamically regulates vascular barrier function, coagulation pathways, leukocyte adhesion, and vasomotor tone. During sepsis and acute inflammation, endothelial cells (ECs) undergo multiple phenotypic and functional modifications that are initially adaptive but eventually become harmful, leading to microvascular dysfunction and multiorgan failure. Critical Issues and Recent Advances: Sepsis unbalances the redox homeostasis toward a pro-oxidant state, characterized by an excess production of reactive oxygen species and reactive nitrogen species, mitochondrial dysfunction, and a breakdown of antioxidant systems. In return, oxidative stress (OS) alters multiple EC functions and promotes a proinflammatory, procoagulant, and proadhesive phenotype. The OS also induces glycocalyx deterioration, cell death, increased permeability, and impaired vasoreactivity. Thus, during sepsis, the ECs are both a significant source and one of the main targets of OS. Future Directions: This review aims at covering the current understanding of the role of OS in the endothelial adaptive or maladaptive multifaceted response to sepsis and to outline the therapeutic potential and issues of targeting OS and endothelial dysfunction during sepsis and septic shock. One of the many challenges in the management of sepsis is now based on the detection and correction of these anomalies of endothelial function. Antioxid. Redox Signal. 00, 000-000.

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Section: Os-induced Ec Deathmentioning

confidence: 99%

Oxidative Stress and Endothelial Dysfunction in Sepsis and Acute Inflammation

Joffre

Hellman

2021

Antioxidants & Redox Signaling

144

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“…The exosome function from dying or apoptotic cells was recently discussed (Kakarla et al, 2020). Dying cells due to infection or tissue injury, release EVs that transfer the proinflammatory information to the recipient cells (Baxter, 2020). THP-1 cells that are undergoing lytic cell death release more EVs compared with viable or apoptotic cells in vitro, and it is essential to distinguish between Tluc associated with EV and free Tluc (Baxter et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

Generation and Application of a Reporter Cell Line for the Quantitative Screen of Extracellular Vesicle Release

et al. 2021

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Extracellular vesicles (EVs) are identified as mediators of intercellular communication and cellular regulation. In the immune system, EVs play a role in antigen presentation as a part of cellular communication. To enable drug discovery and characterization of compounds that affect EV biogenesis, function, and release in immune cells, we developed and characterized a reporter cell line that allows the quantitation of EVs shed into culture media in phenotypic high-throughput screen (HTS) format. Tetraspanins CD63 and CD9 were previously reported to be enriched in EVs; hence, a construct with dual reporters consisting of CD63-Turbo-luciferase (Tluc) and CD9-Emerald green fluorescent protein (EmGFP) was engineered. This construct was transduced into the human monocytic leukemia cell line, THP-1. Cells expressing the highest EmGFP were sorted by flow cytometry as single cell, and clonal pools were expanded under antibiotic selection pressure. After four passages, the green fluorescence dimmed, and EV biogenesis was then tracked by luciferase activity in culture supernatants. The Tluc activities of EVs shed from CD63Tluc-CD9EmGFP reporter cells in the culture supernatant positively correlated with the concentrations of released EVs measured by nanoparticle tracking analysis. To examine the potential for use in HTS, we first miniaturized the assay into a robotic 384-well plate format. A 2210 commercial compound library (Maybridge) was then screened twice on separate days, for the induction of extracellular luciferase activity. The screening data showed high reproducibility on days 1 and 2 (78.6%), a wide signal window, and an excellent Z′ factor (average of 2-day screen, 0.54). One hundred eighty-seven compounds showed a response ratio that was 3SD above the negative controls in both day 1 and 2 screens and were considered as hit candidates (approximately 10%). Twenty-two out of 40 re-tested compounds were validated. These results indicate that the performance of CD63Tluc-CD9EmGFP reporter cells is reliable, reproducible, robust, and feasible for HTS of compounds that regulate EV release by the immune cells.

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“…As demonstrated in this study, the role of gasdermins in cell death is not confined to the transition between modes of death because the gasdermins can control the release of exosomes. Given that ApoExos are probably loaded with the contents of dying cells [37], they transfer information from dying cells to near or distant living cells and tissues, causing the regeneration of damaged tissues, pro-or anti-inflammatory effects, or the arousal of immune responses to autoantigens or cancer antigens [11,12]. Therefore, a complete molecular understanding of the biogenetic mechanisms of ApoExos will be needed to comprehend the pathophysiologic events associated with apoptosis, which can then be used to develop novel therapeutic approaches.…”

Section: Discussionmentioning

confidence: 99%

“…ApoExos have unique markers, including a sphingosine-1-phosphate receptor 1/3 (S1PR1/3), in addition to the known, exosome-specific tetraspanin CD63, which is involved in S1P/S1PR signaling and the subsequent endocytosis of the plasma membrane that occurs during ApoExo biogenesis [12,13]. ApoExos have recently been shown to carry out a variety of functions, such as the induction of inflammation or an autoimmune response, the proliferation of tumors, and increasing cellular survival [11,12].…”

Section: Introductionmentioning

confidence: 99%

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Role of Gasdermins in the Biogenesis of Apoptotic Cell–Derived Exosomes

Kim

et al. 2021

Preprint

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The gasdermins, GSDMA, GSDMB, GSDMC, GSDMD, DFNA5, and DFNB59, are a family of pore-forming proteins that has recently been suggested to play a central role in the pyroptosis and the release of inflammatory cytokines. Here, we describe the novel roles of gasdermins in the biogenesis of apoptotic cell–derived exosomes. In apoptotic cells, GADMA, GSDMC, GSDMD, and DFNA5 increased the release of ApoExos, and both their full-length and cleaved forms were localized in the exosomal membrane. GSDMB and DFNB59, on the other hand, negatively affected the release of ApoExos. The caspase-mediated cleavage of gasdermins, especially DFNA5, is suggested to enable cytosolic Ca2+ to flow through endosomal pores and thus increase the biogenesis of ApoExos. In addition, the DFNA5-meidiated biogenesis of ApoExos depended on the ESCRT-III complex and endosomal recruitment of Ca2+-dependent proteins: annexins A2 and A7, the PEF domain family proteins sorcin and grancalcin, and the Bro1 domain protein HD-PTP. Therefore, we propose that the biogenesis of ApoExos begins when gasdermin-mediated endosomal pores increase cytosolic Ca2+, continues through the recruitment of annexin-sorcin/grancalcin-HD-PTP, and is completed when the ESCRT-III complex synthesizes intraluminal vesicles in the multivesicular bodies of dying cells. Finally, we found that Dfna5-bearing tumors released ApoExos to induce inflammatory responses in the in vivo 4T1 orthotropic model of breast cancer. The data presented in this study indicate that the switch from apoptosis to pyroptosis could drive the transfer of mass signals to nearby or distant living cells and tissues by way of extracellular vesicles, and that gasdermins play critical roles in that process.

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

Cited by 14 publications

References 107 publications

Oxidative Stress and Endothelial Dysfunction in Sepsis and Acute Inflammation

Oxidative Stress and Endothelial Dysfunction in Sepsis and Acute Inflammation

Generation and Application of a Reporter Cell Line for the Quantitative Screen of Extracellular Vesicle Release

Role of Gasdermins in the Biogenesis of Apoptotic Cell–Derived Exosomes

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