TLR4 Response to LPS Is Reinforced by Urokinase Receptor

Front Immunol. 2020 Dec 9:11:573550. doi: 10.3389/fimmu.2020.573550. eCollection 2020.

Abstract

GPI-anchored uPAR is the receptor for the extracellular serine protease urokinase-type plasminogen activator (uPA). Though uPAR role in inflammatory processes is documented, underlying mechanisms are not fully understood. In this study we demonstrate that uPAR is a part of Toll-like receptor 4 (TLR4) interactome. Downregulation of uPAR expression resulted in diminished LPS-induced TLR4 signaling, less activation of NFκB, and decreased secretion of inflammatory mediators in myeloid and non-myeloid cells in vitro. In vivo uPAR-/- mice demonstrated better survival, strongly diminished inflammatory response and better organ functions in cecal ligation and puncture mouse polymicrobial sepsis model. Mechanistically, GPI-uPAR and soluble uPAR colocalized with TLR4 on the cell membrane and interacted with scavenger receptor CD36. Our data show that uPAR can interfere with innate immunity response via TLR4 and this mechanism represents a potentially important target in inflammation and sepsis therapy.

Keywords: CD36; LPS; TLR4; sepsis; urokinase receptor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD36 Antigens / metabolism
  • Cytokines / metabolism
  • Disease Models, Animal
  • Epithelial Cells / drug effects*
  • Epithelial Cells / metabolism
  • Epithelial Cells / microbiology
  • Humans
  • Inflammation / genetics
  • Inflammation / metabolism*
  • Inflammation / microbiology
  • Inflammation / prevention & control
  • Inflammation Mediators / metabolism
  • Lipopolysaccharides / pharmacology*
  • Macrophages, Peritoneal / drug effects*
  • Macrophages, Peritoneal / metabolism
  • Macrophages, Peritoneal / microbiology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • NF-kappa B / metabolism
  • RAW 264.7 Cells
  • Receptors, Urokinase Plasminogen Activator / genetics
  • Receptors, Urokinase Plasminogen Activator / metabolism*
  • Sepsis / genetics
  • Sepsis / metabolism*
  • Sepsis / microbiology
  • Sepsis / prevention & control
  • Signal Transduction
  • Toll-Like Receptor 4 / genetics
  • Toll-Like Receptor 4 / metabolism*

Substances

  • CD36 Antigens
  • Cd36 protein, mouse
  • Cytokines
  • Inflammation Mediators
  • Lipopolysaccharides
  • NF-kappa B
  • PLAUR protein, human
  • Plaur protein, mouse
  • Receptors, Urokinase Plasminogen Activator
  • TLR4 protein, human
  • Tlr4 protein, mouse
  • Toll-Like Receptor 4