AUTHOR=Kiyan Yulia , Tkachuk Sergey , Rong Song , Gorrasi Anna , Ragno Pia , Dumler Inna , Haller Hermann , Shushakova Nelli 

TITLE=TLR4 Response to LPS Is Reinforced by Urokinase Receptor

JOURNAL=Frontiers in Immunology

VOLUME=11

YEAR=2020

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2020.573550

DOI=10.3389/fimmu.2020.573550

ISSN=1664-3224

ABSTRACT=<p>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 <italic>in vitro</italic>. 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 <italic>via</italic> TLR4 and this mechanism represents a potentially important target in inflammation and sepsis therapy.</p>