Circulatory Exosomes from COVID-19 Patients Trigger NLRP3 Inflammasome in Endothelial Cells

mBio. 2022 Jun 28;13(3):e0095122. doi: 10.1128/mbio.00951-22. Epub 2022 May 19.

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection induces inflammatory response, cytokine storm, venous thromboembolism, coagulopathy, and multiple organ damage. Resting endothelial cells prevent coagulation, control blood flow, and inhibit inflammation. However, it remains unknown how SARS-CoV-2 induces strong molecular signals in distant cells for immunopathogenesis. In this study, we examined the consequence of human endothelial cells, microvascular endothelial cells (HMEC-1), and liver endothelial cells (TMNK-1) to exosomes isolated from plasma of mild or severe COVID-19 patients. We observed a significant induction of NLRP3, caspase-1, and interleukin-1β (IL-1β) mRNA expression in endothelial cells following exposure to exosomes from severe COVID-19 patients compared with that from patients with mild disease or healthy donors. Activation of caspase-1 was noted in the endothelial cell culture medium following exposure to the COVID-19 exosomes. Furthermore, COVID-19 exosomes significantly induced mature IL-1β secretion in both HMEC-1 and TMNK-1 endothelial cell culture medium. Thus, our results demonstrated for the first time that exosomes from COVID-19 plasma trigger NLRP3 inflammasome in endothelial cells of distant organs resulting in IL-1β secretion and inflammatory response. IMPORTANCE Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is a global health problem. Although the vaccine controls infection, understanding the molecular mechanism of pathogenesis will help in developing future therapies. Furthermore, several investigators predicted the involvement of endothelial cell-related inflammation in SARS-CoV-2 infection and using extracellular vesicles as a cargo to carry a drug or vaccine for combating SARS-CoV-2 infection. However, the mechanism by which endothelial cells are inflamed remains unknown. Our present study highlights that exosomes from severe COVID-19 patients can enhance inflammasome activity in distant endothelial cells for augmentation of immunopathogenesis and opens an avenue for developing therapies.

Keywords: COVID-19; NLRP3; SARS-CoV-2; endothelial cells; exosomes; inflammasome.

MeSH terms

  • COVID-19*
  • Caspases
  • Endothelial Cells / metabolism
  • Exosomes* / metabolism
  • Humans
  • Inflammasomes / metabolism
  • Inflammation
  • NLR Family, Pyrin Domain-Containing 3 Protein / genetics
  • NLR Family, Pyrin Domain-Containing 3 Protein / metabolism
  • SARS-CoV-2

Substances

  • Inflammasomes
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Caspases