Endotoxin tolerance and low activation of TLR-4/NF-κB axis in monocytes of COVID-19 patients

J Mol Med (Berl). 2023 Feb;101(1-2):183-195. doi: 10.1007/s00109-023-02283-x. Epub 2023 Feb 15.

Abstract

Higher endotoxin in the circulation may indicate a compromised state of host immune response against coinfections in severe COVID-19 patients. We evaluated the inflammatory response of monocytes from COVID-19 patients after lipopolysaccharide (LPS) challenge. Whole blood samples of healthy controls, patients with mild COVID-19, and patients with severe COVID-19 were incubated with LPS for 2 h. Severe COVID-19 patients presented higher LPS and sCD14 levels in the plasma than healthy controls and mild COVID-19 patients. In non-stimulated in vitro condition, severe COVID-19 patients presented higher inflammatory cytokines and PGE-2 levels and CD14 + HLA-DRlow monocytes frequency than controls. Moreover, severe COVID-19 patients presented higher NF-κB p65 phosphorylation in CD14 + HLA-DRlow, as well as higher expression of TLR-4 and NF-κB p65 phosphorylation in CD14 + HLA-DRhigh compared to controls. The stimulation of LPS in whole blood of severe COVID-19 patients leads to lower cytokine production but higher PGE-2 levels compared to controls. Endotoxin challenge with both concentrations reduced the frequency of CD14 + HLA-DRlow in severe COVID-19 patients, but the increases in TLR-4 expression and NF-κB p65 phosphorylation were more pronounced in both CD14 + monocytes of healthy controls and mild COVID-19 patients compared to severe COVID-19 group. We conclude that acute SARS-CoV-2 infection is associated with diminished endotoxin response in monocytes. KEY MESSAGES: Severe COVID-19 patients had higher levels of LPS and systemic IL-6 and TNF-α. Severe COVID-19 patients presented higher CD14+HLA-DRlow monocytes. Increased TLR-4/NF-κB axis was identified in monocytes of severe COVID-19. Blunted production of cytokines after whole blood LPS stimulation in severe COVID-19. Lower TLR-4/NF-κB activation in monocytes after LPS stimulation in severe COVID-19.

Keywords: COVID-19; Inflammation; Lipopolysaccharide; Monocytes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • COVID-19* / metabolism
  • Cytokines / metabolism
  • Endotoxin Tolerance
  • HLA-DR Antigens / metabolism
  • Humans
  • Lipopolysaccharide Receptors / metabolism
  • Lipopolysaccharides
  • Monocytes* / metabolism
  • NF-kappa B / metabolism
  • SARS-CoV-2 / metabolism
  • Toll-Like Receptor 4 / metabolism
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • NF-kappa B
  • Toll-Like Receptor 4
  • Lipopolysaccharides
  • Cytokines
  • Tumor Necrosis Factor-alpha
  • HLA-DR Antigens
  • Lipopolysaccharide Receptors