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Toll-like receptor-4 coordinates the innate immune response of the kidney to renal ischemia/reperfusion injury.

Pulskens WP, Teske GJ, Butter LM, Roelofs JJ, van der Poll T, Florquin S, Leemans JC - PLoS ONE (2008)

Bottom Line: The functional relevance of this organ-specific upregulation remains however unknown.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. w.p.pulskens@amc.uva.nl

ABSTRACT
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.

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Equal contribution of epithelium-associated and leukocyte-associated TLR4 on renal function and injury one day after I/R injury.Renal function and injury of wild type mice reconstituted with TLR4−/− bone marrow (WT+KO BM, white bars, n = 7) was comparable to TLR4−/− mice reconstituted with wild type bone marrow (KO+WT BM, black bars, n = 9) one day after renal I/R injury, as reflected by equal levels of ureum (A left) and creatinine (A right) and tubular injury (B). Data are mean±SEM. * p<0.05.
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pone-0003596-g006: Equal contribution of epithelium-associated and leukocyte-associated TLR4 on renal function and injury one day after I/R injury.Renal function and injury of wild type mice reconstituted with TLR4−/− bone marrow (WT+KO BM, white bars, n = 7) was comparable to TLR4−/− mice reconstituted with wild type bone marrow (KO+WT BM, black bars, n = 9) one day after renal I/R injury, as reflected by equal levels of ureum (A left) and creatinine (A right) and tubular injury (B). Data are mean±SEM. * p<0.05.

Mentions: In order to investigate whether the observed functional and morphological differences between wild type and TLR4−/− mice upon renal I/R injury could be ascribed to either renal epithelium-associated TLR4 or leukocyte-associated TLR4, bone marrow (BM) transplantation was performed to create chimeric mice. After seven weeks of engraftment, at least 80% of the leukocyte population of all mice consisted of donor-derived cells, indicating extensive engraftment (data not shown). These mice were subsequently subjected to severe renal I/R injury. It became clear that mice with renal-associated TLR4 (WT+KO BM) showed an equal degree of renal dysfunction compared to mice with leukocyte-associated TLR4 (KO+WT BM) one day after I/R injury as reflected by similar plasma levels of urea and creatinine (figure 6a). In addition, semi quantitative scoring of PASD-stained sections revealed that there was an equal level of renal injury between both groups (figure 6b). These results suggest that both renal-associated and leukocyte-associated TLR4 contribute to the observed functional and morphological differences that resulted from TLR4 deficiency upon renal I/R injury.


Toll-like receptor-4 coordinates the innate immune response of the kidney to renal ischemia/reperfusion injury.

Pulskens WP, Teske GJ, Butter LM, Roelofs JJ, van der Poll T, Florquin S, Leemans JC - PLoS ONE (2008)

Equal contribution of epithelium-associated and leukocyte-associated TLR4 on renal function and injury one day after I/R injury.Renal function and injury of wild type mice reconstituted with TLR4−/− bone marrow (WT+KO BM, white bars, n = 7) was comparable to TLR4−/− mice reconstituted with wild type bone marrow (KO+WT BM, black bars, n = 9) one day after renal I/R injury, as reflected by equal levels of ureum (A left) and creatinine (A right) and tubular injury (B). Data are mean±SEM. * p<0.05.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2570789&req=5

pone-0003596-g006: Equal contribution of epithelium-associated and leukocyte-associated TLR4 on renal function and injury one day after I/R injury.Renal function and injury of wild type mice reconstituted with TLR4−/− bone marrow (WT+KO BM, white bars, n = 7) was comparable to TLR4−/− mice reconstituted with wild type bone marrow (KO+WT BM, black bars, n = 9) one day after renal I/R injury, as reflected by equal levels of ureum (A left) and creatinine (A right) and tubular injury (B). Data are mean±SEM. * p<0.05.
Mentions: In order to investigate whether the observed functional and morphological differences between wild type and TLR4−/− mice upon renal I/R injury could be ascribed to either renal epithelium-associated TLR4 or leukocyte-associated TLR4, bone marrow (BM) transplantation was performed to create chimeric mice. After seven weeks of engraftment, at least 80% of the leukocyte population of all mice consisted of donor-derived cells, indicating extensive engraftment (data not shown). These mice were subsequently subjected to severe renal I/R injury. It became clear that mice with renal-associated TLR4 (WT+KO BM) showed an equal degree of renal dysfunction compared to mice with leukocyte-associated TLR4 (KO+WT BM) one day after I/R injury as reflected by similar plasma levels of urea and creatinine (figure 6a). In addition, semi quantitative scoring of PASD-stained sections revealed that there was an equal level of renal injury between both groups (figure 6b). These results suggest that both renal-associated and leukocyte-associated TLR4 contribute to the observed functional and morphological differences that resulted from TLR4 deficiency upon renal I/R injury.

Bottom Line: The functional relevance of this organ-specific upregulation remains however unknown.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. w.p.pulskens@amc.uva.nl

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus