Cell Death Discovery (Apr 2024)

SARS-CoV-2 and its ORF3a, E and M viroporins activate inflammasome in human macrophages and induce of IL-1α in pulmonary epithelial and endothelial cells

  • Magdalena Ambrożek-Latecka,
  • Piotr Kozlowski,
  • Grażyna Hoser,
  • Magdalena Bandyszewska,
  • Karolina Hanusek,
  • Dominika Nowis,
  • Jakub Gołąb,
  • Małgorzata Grzanka,
  • Agnieszka Piekiełko-Witkowska,
  • Luise Schulz,
  • Franziska Hornung,
  • Stefanie Deinhardt-Emmer,
  • Ewa Kozlowska,
  • Tomasz Skirecki

DOI
https://doi.org/10.1038/s41420-024-01966-9
Journal volume & issue
Vol. 10, no. 1
pp. 1 – 11

Abstract

Read online

Abstract Inflammasome assembly is a potent mechanism responsible for the host protection against pathogens, including viruses. When compromised, it can allow viral replication, while when disrupted, it can perpetuate pathological responses by IL-1 signaling and pyroptotic cell death. SARS-CoV-2 infection was shown to activate inflammasome in the lungs of COVID-19 patients, however, potential mechanisms responsible for this response are not fully elucidated. In this study, we investigated the effects of ORF3a, E and M SARS-CoV-2 viroporins in the inflammasome activation in major populations of alveolar sentinel cells: macrophages, epithelial and endothelial cells. We demonstrated that each viroporin is capable of activation of the inflammasome in macrophages to trigger pyroptosis-like cell death and IL-1α release from epithelial and endothelial cells. Small molecule NLRP3 inflammasome inhibitors reduced IL-1 release but weakly affected the pyroptosis. Importantly, we discovered that while SARS-CoV-2 could not infect the pulmonary microvascular endothelial cells it induced IL-1α and IL-33 release. Together, these findings highlight the essential role of macrophages as the major inflammasome-activating cell population in the lungs and point to endothelial cell expressed IL-1α as a potential novel component driving the pulmonary immunothromobosis in COVID-19.