Publication Date:
2022-08-22
Description:
© The Author(s), 2022. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Aymonnier, K., Ng, J., Fredenburgh, L. E., Zambrano-Vera, K., Muenzer, P., Gutch, S., Fukui, S., Desjardins, M., Subramaniam, M., Baron, R. M., Raby, B. A., Perrella, M. A., Lederer, J. A., & Wagner, D. D. Inflammasome activation in neutrophils of patients with severe COVID-19. Blood Advances, 6(7), (2022): 2001–2013, https://doi.org/10.1182/bloodadvances.2021005949.
Description:
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 (ie, apoptosis-associated speck-like protein containing a CARD [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 ∼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 lipopolysaccharide -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.
Description:
P.M. received an Individual Marie Skłodowska-Curie Actions fellowship by the European Commission (796365 - COAGULANT). This work was supported by the National Institutes of Health (NIH)/Research Program Award grant R35 HL135765 (D.W.), by the NIH/National Heart, Lung, and Blood Institute grant T32 HL007633-35 (J.N.), and by the NIH/National Institute of Allergy and Infectious Diseases grant U01AI138318 (J.L and M.P); by the Massachusetts Consortium on Pathogen Readiness (MassCPR) Evergrande COVID‐19 Response Fund Award to B.R.; and by a generous gift to D.W. from the Steven Berzin family.
Keywords:
Phagocytes
;
Granulocytes
;
Myelopoiesis
Repository Name:
Woods Hole Open Access Server
Type:
Article
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