Detection of In Vivo Inflammasome Activation for Predicting Sepsis Mortality

Cui, Jing; Oehrl, Stephanie; Faried, Ahmad; Brenner, Thorsten; Uhle, Florian; Nußhag, Christian; Rupp, Christoph; Funck, Felix; Meisel, Stefan; Weigand, Markus A.; Morath, Christian; Schäkel, Knut

doi:10.3389/fimmu.2020.613745

Cited by 15 publications

(13 citation statements)

References 73 publications

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“…These findings support the possibility that both neutrophils and monocytes contribute to the cytokine storm through the inflammasome, and in vivo ASC-speck detection could serve as an indicator of innate immune system activation. In bacterial sepsis, Cui et al has shown that assessing ASC speck positive immune cells by flow cytometry could be used as a potential biomarker of patients at risk of death 25 .…”

Section: Discussionmentioning

confidence: 99%

Inflammasome activation in neutrophils of patients with severe COVID-19

Aymonnier

Fredenburgh

et al. 2022

Blood Advances

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Infection by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) engages the inflammasome in monocytes and macrophages and leads to the cytokine storm in COVID-19. Neutrophils, the most abundant leukocytes, release neutrophil extracellular traps (NETs), which have been implicated in the pathogenesis of COVID-19. Our recent study shows that activation of the NLRP3 inflammasome is important for NET release in sterile inflammation. However, the role of neutrophil inflammasome formation in human disease is unknown. We hypothesized that SARS-COV-2 infection may induce inflammasome activation in neutrophils. We also aimed to assess the localization of inflammasome formation, (i.e. ASC speck assembly), and timing relative to NETosis in stimulated neutrophils by real time video microscopy. Neutrophils isolated from severe COVID-19 patients demonstrated that approximately 2% of neutrophils in both the peripheral blood and tracheal aspirates presented ASC speck. ASC speck was observed in neutrophils with an intact poly-lobulated nucleus, suggesting early formation during neutrophil activation. Additionally, 40% of nuclei were positive for citrullinated histone H3, and there was a significant correlation between speck formation and nuclear histone citrullination. Time-lapse microscopy in LPS-stimulated neutrophils from fluorescent ASC reporter mice showed that ASC speck formed transiently and at the microtubule organizing center, long before NET release. Our study shows that ASC speck is present in neutrophils from COVID-19 patients with respiratory failure and that it forms early in NETosis. Our findings suggest that inhibition of neutrophil inflammasomes may be beneficial in COVID-19.

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Section: Discussionmentioning

confidence: 99%

Inflammasome activation in neutrophils of patients with severe COVID-19

Aymonnier

Fredenburgh

et al. 2022

Blood Advances

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“…Pyroptosis is an ideal tool for the clearance of infected cells because it is a form of lytic cell death that causes release of abundant inflammatory cytokines and enables destruction of intracellular replicative niches. This might be the positive role of pyroptosis in infection, but if out of control, it could be detrimental to the host [21][22][23][24]. Pyroptosis contributes to the hyperinflammatory response in sepsis, and recent advances indicate its role in adaptive immunity, which is closely related to immune paralysis.…”

Section: What Do We Know About Pyroptosis In Sepsismentioning

confidence: 99%

Autophagy Regulation on Pyroptosis: Mechanism and Medical Implication in Sepsis

Guo

Wang

Cui

2021

Mediators of Inflammation

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Sepsis is defined as a life-threatening disease involving multiple organ dysfunction caused by dysregulated host responses to infection. To date, sepsis remains a dominant cause of death among critically ill patients. Pyroptosis is a unique form of programmed cell death mediated by the gasdermin family of proteins and causes lytic cell death and release of proinflammatory cytokines. Although there might be some positive aspects to pyroptosis, it is regarded as harmful during sepsis and needs to be restricted. Autophagy was originally characterized as a homeostasis-maintaining mechanism in living cells. In the past decade, its function in negatively modulating pyroptosis and inflammation during sepsis has attracted increased attention. Here, we present a comprehensive review of the regulatory effect of autophagy on pyroptosis during sepsis, including the latest advances in our understanding of the mechanism and signaling pathways involved, as well as the potential therapeutic application in sepsis.

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“…When evaluating ASC-speck formation in monocytes during the first week of sepsis in patients, the highest number of ASC-speck + monocytes can be detected on day 6-7. Survival analysis shows that patients with lower numbers of ASC-speck + monocytes (<1650 cells/mL) on day 6 has greater risk of mortality [60].…”

Section: Elements Of Immunopathogenesis and Molecular Signature Of Se...mentioning

confidence: 99%

Immunomonitoring of Monocyte and Neutrophil Function in Critically Ill Patients: From Sepsis and/or Trauma to COVID-19

Udovičić

Stanojević

Djordjević

et al. 2021

JCM

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Immune cells and mediators play a crucial role in the critical care setting but are understudied. This review explores the concept of sepsis and/or injury-induced immunosuppression and immuno-inflammatory response in COVID-19 and reiterates the need for more accurate functional immunomonitoring of monocyte and neutrophil function in these critically ill patients. in addition, the feasibility of circulating and cell-surface immune biomarkers as predictors of infection and/or outcome in critically ill patients is explored. It is clear that, for critically ill, one size does not fit all and that immune phenotyping of critically ill patients may allow the development of a more personalized approach with tailored immunotherapy for the specific patient. In addition, at this point in time, caution is advised regarding the quality of evidence of some COVID-19 studies in the literature.

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Detection of In Vivo Inflammasome Activation for Predicting Sepsis Mortality

Cited by 15 publications

References 73 publications

Inflammasome activation in neutrophils of patients with severe COVID-19

Inflammasome activation in neutrophils of patients with severe COVID-19

Autophagy Regulation on Pyroptosis: Mechanism and Medical Implication in Sepsis

Immunomonitoring of Monocyte and Neutrophil Function in Critically Ill Patients: From Sepsis and/or Trauma to COVID-19

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