tetano
Editor, Senior Moderator
Blood Adv
. 2022 Jan 6;bloodadvances.2021005949.
doi: 10.1182/bloodadvances.2021005949. Online ahead of print.
Inflammasome activation in neutrophils of patients with severe COVID-19
Karen Aymonnier[SUP] 1 [/SUP], Julie Ng[SUP] 2 [/SUP], Laura E Fredenburgh[SUP] 2 [/SUP], Katherin Zambrano-Vera[SUP] 2 [/SUP], Patrick Münzer[SUP] 3 [/SUP], Sarah Gutch[SUP] 4 [/SUP], Shoichi Fukui[SUP] 3 [/SUP], Michael Desjardins[SUP] 2 [/SUP], Meera Subramaniam[SUP] 4 [/SUP], Rebecca Baron[SUP] 2 [/SUP], Benjamin A Raby[SUP] 4 [/SUP], Mark A Perrella[SUP] 2 [/SUP], James A Lederer[SUP] 5 [/SUP], Denisa D Wagner[SUP] 5 [/SUP]
Affiliations
Abstract
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.
. 2022 Jan 6;bloodadvances.2021005949.
doi: 10.1182/bloodadvances.2021005949. Online ahead of print.
Inflammasome activation in neutrophils of patients with severe COVID-19
Karen Aymonnier[SUP] 1 [/SUP], Julie Ng[SUP] 2 [/SUP], Laura E Fredenburgh[SUP] 2 [/SUP], Katherin Zambrano-Vera[SUP] 2 [/SUP], Patrick Münzer[SUP] 3 [/SUP], Sarah Gutch[SUP] 4 [/SUP], Shoichi Fukui[SUP] 3 [/SUP], Michael Desjardins[SUP] 2 [/SUP], Meera Subramaniam[SUP] 4 [/SUP], Rebecca Baron[SUP] 2 [/SUP], Benjamin A Raby[SUP] 4 [/SUP], Mark A Perrella[SUP] 2 [/SUP], James A Lederer[SUP] 5 [/SUP], Denisa D Wagner[SUP] 5 [/SUP]
Affiliations
- PMID: 34991159
- DOI: 10.1182/bloodadvances.2021005949
Abstract
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.