Cargando…

Toll-Like Receptor-4 Coordinates the Innate Immune Response of the Kidney to Renal Ischemia/Reperfusion Injury

Toll-like receptors (TLRs) can detect endogenous danger molecules released upon tissue injury resulting in the induction of a proinflammatory response. One of the TLR family members, TLR4, is constitutively expressed at RNA level on renal epithelium and this expression is enhanced upon renal ischemi...

Descripción completa

Detalles Bibliográficos
Autores principales: Pulskens, Wilco P., Teske, Gwendoline J., Butter, Loes M., Roelofs, Joris J., van der Poll, Tom, Florquin, Sandrine, Leemans, Jaklien C.
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2008
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2570789/
https://www.ncbi.nlm.nih.gov/pubmed/18974879
http://dx.doi.org/10.1371/journal.pone.0003596
_version_ 1782160171727847424
author Pulskens, Wilco P.
Teske, Gwendoline J.
Butter, Loes M.
Roelofs, Joris J.
van der Poll, Tom
Florquin, Sandrine
Leemans, Jaklien C.
author_facet Pulskens, Wilco P.
Teske, Gwendoline J.
Butter, Loes M.
Roelofs, Joris J.
van der Poll, Tom
Florquin, Sandrine
Leemans, Jaklien C.
author_sort Pulskens, Wilco P.
collection PubMed
description Toll-like receptors (TLRs) can detect endogenous danger molecules released upon tissue injury resulting in the induction of a proinflammatory response. One of the TLR family members, TLR4, is constitutively expressed at RNA level on renal epithelium and this expression is enhanced upon renal ischemia/reperfusion (I/R) injury. The functional relevance of this organ-specific upregulation remains however unknown. We therefore investigated the specific role of TLR4 and the relative contribution of its two downstream signaling cascades, the MyD88-dependent and TRIF-dependent cascades in renal damage by using TLR4−/−, MyD88−/− and TRIF-mutant mice that were subjected to renal ischemia/reperfusion injury. Our results show that TLR4 initiates an exaggerated proinflammatory response upon I/R injury, as reflected by lower levels of chemokines and infiltrating granulocytes, less renal damage and a more preserved renal function in TLR4−/− mice as compared to wild type mice. In vitro studies demonstrate that renal tubular epithelial cells can coordinate an immune response to ischemic injury in a TLR4-dependent manner. In vivo we found that epithelial- and leukocyte-associated functional TLR4 contribute in a similar proportion to renal dysfunction and injury as assessed by bone marrow chimeric mice. Surprisingly, no significant differences were found in renal function and inflammation in MyD88−/− and TRIF-mutant mice compared with their wild types, suggesting that selective targeting of TLR4 directly may be more effective for the development of therapeutic tools to prevent I/R injury than targeting the intracellular pathways used by TLR4. In conclusion, we identified TLR4 as a cellular sentinel for acute renal damage that subsequently controls the induction of an innate immune response.
format Text
id pubmed-2570789
institution National Center for Biotechnology Information
language English
publishDate 2008
publisher Public Library of Science
record_format MEDLINE/PubMed
spelling pubmed-25707892008-10-31 Toll-Like Receptor-4 Coordinates the Innate Immune Response of the Kidney to Renal Ischemia/Reperfusion Injury Pulskens, Wilco P. Teske, Gwendoline J. Butter, Loes M. Roelofs, Joris J. van der Poll, Tom Florquin, Sandrine Leemans, Jaklien C. PLoS One Research Article Toll-like receptors (TLRs) can detect endogenous danger molecules released upon tissue injury resulting in the induction of a proinflammatory response. One of the TLR family members, TLR4, is constitutively expressed at RNA level on renal epithelium and this expression is enhanced upon renal ischemia/reperfusion (I/R) injury. The functional relevance of this organ-specific upregulation remains however unknown. We therefore investigated the specific role of TLR4 and the relative contribution of its two downstream signaling cascades, the MyD88-dependent and TRIF-dependent cascades in renal damage by using TLR4−/−, MyD88−/− and TRIF-mutant mice that were subjected to renal ischemia/reperfusion injury. Our results show that TLR4 initiates an exaggerated proinflammatory response upon I/R injury, as reflected by lower levels of chemokines and infiltrating granulocytes, less renal damage and a more preserved renal function in TLR4−/− mice as compared to wild type mice. In vitro studies demonstrate that renal tubular epithelial cells can coordinate an immune response to ischemic injury in a TLR4-dependent manner. In vivo we found that epithelial- and leukocyte-associated functional TLR4 contribute in a similar proportion to renal dysfunction and injury as assessed by bone marrow chimeric mice. Surprisingly, no significant differences were found in renal function and inflammation in MyD88−/− and TRIF-mutant mice compared with their wild types, suggesting that selective targeting of TLR4 directly may be more effective for the development of therapeutic tools to prevent I/R injury than targeting the intracellular pathways used by TLR4. In conclusion, we identified TLR4 as a cellular sentinel for acute renal damage that subsequently controls the induction of an innate immune response. Public Library of Science 2008-10-31 /pmc/articles/PMC2570789/ /pubmed/18974879 http://dx.doi.org/10.1371/journal.pone.0003596 Text en Pulskens et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Pulskens, Wilco P.
Teske, Gwendoline J.
Butter, Loes M.
Roelofs, Joris J.
van der Poll, Tom
Florquin, Sandrine
Leemans, Jaklien C.
Toll-Like Receptor-4 Coordinates the Innate Immune Response of the Kidney to Renal Ischemia/Reperfusion Injury
title Toll-Like Receptor-4 Coordinates the Innate Immune Response of the Kidney to Renal Ischemia/Reperfusion Injury
title_full Toll-Like Receptor-4 Coordinates the Innate Immune Response of the Kidney to Renal Ischemia/Reperfusion Injury
title_fullStr Toll-Like Receptor-4 Coordinates the Innate Immune Response of the Kidney to Renal Ischemia/Reperfusion Injury
title_full_unstemmed Toll-Like Receptor-4 Coordinates the Innate Immune Response of the Kidney to Renal Ischemia/Reperfusion Injury
title_short Toll-Like Receptor-4 Coordinates the Innate Immune Response of the Kidney to Renal Ischemia/Reperfusion Injury
title_sort toll-like receptor-4 coordinates the innate immune response of the kidney to renal ischemia/reperfusion injury
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2570789/
https://www.ncbi.nlm.nih.gov/pubmed/18974879
http://dx.doi.org/10.1371/journal.pone.0003596
work_keys_str_mv AT pulskenswilcop tolllikereceptor4coordinatestheinnateimmuneresponseofthekidneytorenalischemiareperfusioninjury
AT teskegwendolinej tolllikereceptor4coordinatestheinnateimmuneresponseofthekidneytorenalischemiareperfusioninjury
AT butterloesm tolllikereceptor4coordinatestheinnateimmuneresponseofthekidneytorenalischemiareperfusioninjury
AT roelofsjorisj tolllikereceptor4coordinatestheinnateimmuneresponseofthekidneytorenalischemiareperfusioninjury
AT vanderpolltom tolllikereceptor4coordinatestheinnateimmuneresponseofthekidneytorenalischemiareperfusioninjury
AT florquinsandrine tolllikereceptor4coordinatestheinnateimmuneresponseofthekidneytorenalischemiareperfusioninjury
AT leemansjaklienc tolllikereceptor4coordinatestheinnateimmuneresponseofthekidneytorenalischemiareperfusioninjury