TLR4 Response to LPS Is Reinforced by Urokinase Receptor

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.

Calcium dobesilate reduces SARS-CoV-2 entry into endothelial cells by inhibiting virus binding to heparan sulfate

“…The effect of CaD on pinocytosis was assessed using FITC-Dextran (40,000 kDa, Sigma, Merck KGaA, Darmstadt, Germany). Effect of CaD on phagocytosis was measured using FITC-labelled E.coli as described recently 68 ⁠. Fluorescence was measured using TECAN ELISA reader with Magellan software (Version 3.0x; https://www.tecan.com/ ).…”

The uPA/uPAR System Orchestrates the Inflammatory Response, Vascular Homeostasis, and Immune System in Fibrosis Progression

“…In contrast, uPAR interacts with several receptors, including integrins and LRP, and participates in the initiation of the innate immune response through the induction of cell adhesion and migration [ 200 ]. In addition, uPAR regulates toll-like receptor (TLR) 2, 4, and 7 signaling, and affects inflammation (cytokine production, mediation of NF-κB pathway) and immune responses (neutrophil and macrophage activation, macrophage efferocytosis) [ 38 , 209 , 210 , 211 ]. The expression and release of suPAR is induced by inflammation and immune activation [ 212 ].…”

Plasminogen activator receptor assemblies in cell signaling, innate immunity, and inflammation

“…Moreover, uPA and the uPA cell-signaling receptor assembly regulate TLR activity. Kiyan et al (163) demonstrated that uPAR is a member of the TLR4 interactome. uPAR-deficient leukocytes demonstrate attenuated cell-signaling responses and decreased pro-inflammatory cytokine expression when treated with the TLR4 agonist, lipopolysaccharide (LPS).…”

“…uPAR-deficient leukocytes demonstrate attenuated cell-signaling responses and decreased pro-inflammatory cytokine expression when treated with the TLR4 agonist, lipopolysaccharide (LPS). The toxicity of systemically administered LPS is attenuated in uPAR-deficient mice (163). uPAR deficiency also protects mice from the effects of LPS on kidney barrier function (164).…”