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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...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2020
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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. |
format | Online Article Text |
id | pubmed-7757075 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
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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