The spike protein of SARS-CoV-2 induces endothelial inflammation through integrin α5β1 and NF-κB signaling

J Biol Chem. 2022 Mar;298(3):101695. doi: 10.1016/j.jbc.2022.101695. Epub 2022 Feb 7.


Vascular endothelial cells (ECs) form a critical interface between blood and tissues that maintains whole-body homeostasis. In COVID-19, disruption of the EC barrier results in edema, vascular inflammation, and coagulation, hallmarks of this severe disease. However, the mechanisms by which ECs are dysregulated in COVID-19 are unclear. Here, we show that the spike protein of SARS-CoV-2 alone activates the EC inflammatory phenotype in a manner dependent on integrin ⍺5β1 signaling. Incubation of human umbilical vein ECs with whole spike protein, its receptor-binding domain, or the integrin-binding tripeptide RGD induced the nuclear translocation of NF-κB and subsequent expression of leukocyte adhesion molecules (VCAM1 and ICAM1), coagulation factors (TF and FVIII), proinflammatory cytokines (TNFα, IL-1β, and IL-6), and ACE2, as well as the adhesion of peripheral blood leukocytes and hyperpermeability of the EC monolayer. In addition, inhibitors of integrin ⍺5β1 activation prevented these effects. Furthermore, these vascular effects occur in vivo, as revealed by the intravenous administration of spike, which increased expression of ICAM1, VCAM1, CD45, TNFα, IL-1β, and IL-6 in the lung, liver, kidney, and eye, and the intravitreal injection of spike, which disrupted the barrier function of retinal capillaries. We suggest that the spike protein, through its RGD motif in the receptor-binding domain, binds to integrin ⍺5β1 in ECs to activate the NF-κB target gene expression programs responsible for vascular leakage and leukocyte adhesion. These findings uncover a new direct action of SARS-CoV-2 on EC dysfunction and introduce integrin ⍺5β1 as a promising target for treating vascular inflammation in COVID-19.

Keywords: ACE2; COVID-19; NF-κB; SARS-CoV-2; endothelial cell; endothelial dysfunction; inflammation; integrin; permeability; spike protein.

MeSH terms

  • COVID-19* / metabolism
  • COVID-19* / pathology
  • COVID-19* / virology
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Inflammation* / metabolism
  • Inflammation* / pathology
  • Inflammation* / virology
  • Integrin alpha5beta1* / metabolism
  • Interleukin-6 / metabolism
  • NF-kappa B* / metabolism
  • Oligopeptides
  • SARS-CoV-2
  • Signal Transduction
  • Spike Glycoprotein, Coronavirus* / metabolism
  • Tumor Necrosis Factor-alpha* / metabolism


  • Integrin alpha5beta1
  • Interleukin-6
  • NF-kappa B
  • Oligopeptides
  • Spike Glycoprotein, Coronavirus
  • Tumor Necrosis Factor-alpha
  • spike protein, SARS-CoV-2
  • arginyl-glycyl-aspartic acid