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TLR4 Response to LPS Is Reinforced by Urokinase Receptor

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...

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Autores principales: Kiyan, Yulia, Tkachuk, Sergey, Rong, Song, Gorrasi, Anna, Ragno, Pia, Dumler, Inna, Haller, Hermann, Shushakova, Nelli
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7757075/
https://www.ncbi.nlm.nih.gov/pubmed/33362762
http://dx.doi.org/10.3389/fimmu.2020.573550
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author Kiyan, Yulia
Tkachuk, Sergey
Rong, Song
Gorrasi, Anna
Ragno, Pia
Dumler, Inna
Haller, Hermann
Shushakova, Nelli
author_facet Kiyan, Yulia
Tkachuk, Sergey
Rong, Song
Gorrasi, Anna
Ragno, Pia
Dumler, Inna
Haller, Hermann
Shushakova, Nelli
author_sort Kiyan, Yulia
collection PubMed
description 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.
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spelling pubmed-77570752020-12-24 TLR4 Response to LPS Is Reinforced by Urokinase Receptor Kiyan, Yulia Tkachuk, Sergey Rong, Song Gorrasi, Anna Ragno, Pia Dumler, Inna Haller, Hermann Shushakova, Nelli Front Immunol Immunology 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. Frontiers Media S.A. 2020-12-09 /pmc/articles/PMC7757075/ /pubmed/33362762 http://dx.doi.org/10.3389/fimmu.2020.573550 Text en Copyright © 2020 Kiyan, Tkachuk, Rong, Gorrasi, Ragno, Dumler, Haller and Shushakova http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Kiyan, Yulia
Tkachuk, Sergey
Rong, Song
Gorrasi, Anna
Ragno, Pia
Dumler, Inna
Haller, Hermann
Shushakova, Nelli
TLR4 Response to LPS Is Reinforced by Urokinase Receptor
title TLR4 Response to LPS Is Reinforced by Urokinase Receptor
title_full TLR4 Response to LPS Is Reinforced by Urokinase Receptor
title_fullStr TLR4 Response to LPS Is Reinforced by Urokinase Receptor
title_full_unstemmed TLR4 Response to LPS Is Reinforced by Urokinase Receptor
title_short TLR4 Response to LPS Is Reinforced by Urokinase Receptor
title_sort tlr4 response to lps is reinforced by urokinase receptor
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7757075/
https://www.ncbi.nlm.nih.gov/pubmed/33362762
http://dx.doi.org/10.3389/fimmu.2020.573550
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