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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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Renal influx of granulocytes in wild type and TLR4βˆ’/βˆ’ mice.Influx of granulocytes in kidneys from wild type (white bars) and TLR4βˆ’/βˆ’ (black bars) kidneys 1, 5 and 10 days after renal I/R injury or sham operation. One and ten days after I/R injury the number of granulocytes was significantly lower in kidneys of TLR4βˆ’/βˆ’ mice than in kidneys of wild type mice as counted in 10 randomly selected high-power fields (HPFs) on outer medulla (magnification Γ—400). The amount of granulocytes from 8 mice per group were counted on renal tissue sections stained for Ly-6G and presented as meanΒ±SEM. * p<0.05.
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pone-0003596-g003: Renal influx of granulocytes in wild type and TLR4βˆ’/βˆ’ mice.Influx of granulocytes in kidneys from wild type (white bars) and TLR4βˆ’/βˆ’ (black bars) kidneys 1, 5 and 10 days after renal I/R injury or sham operation. One and ten days after I/R injury the number of granulocytes was significantly lower in kidneys of TLR4βˆ’/βˆ’ mice than in kidneys of wild type mice as counted in 10 randomly selected high-power fields (HPFs) on outer medulla (magnification Γ—400). The amount of granulocytes from 8 mice per group were counted on renal tissue sections stained for Ly-6G and presented as meanΒ±SEM. * p<0.05.

Mentions: In order to obtain insight into the role of TLR4 in renal inflammation, we compared granulocyte and macrophage influx in kidneys of TLR4βˆ’/βˆ’ and wild type mice by immunohistochemistry. Kidneys of wild type mice showed a transient increase in granulocyte influx with a peak one day after I/R injury (figure 3). Interestingly, TLR4βˆ’/βˆ’ kidneys showed significantly lower amounts of infiltrated granulocytes one and ten days after I/R injury compared with wild type kidneys. Analysis of macrophage influx revealed that there was an increased infiltration of these cells in the corticomedullary region with a peak ten days after I/R injury in kidneys which was similar in both TLR4βˆ’/βˆ’ and wild type mice (3.020Β±0.862 vs. 3.240Β±0.600 percentage staining/HPF).


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)

Renal influx of granulocytes in wild type and TLR4βˆ’/βˆ’ mice.Influx of granulocytes in kidneys from wild type (white bars) and TLR4βˆ’/βˆ’ (black bars) kidneys 1, 5 and 10 days after renal I/R injury or sham operation. One and ten days after I/R injury the number of granulocytes was significantly lower in kidneys of TLR4βˆ’/βˆ’ mice than in kidneys of wild type mice as counted in 10 randomly selected high-power fields (HPFs) on outer medulla (magnification Γ—400). The amount of granulocytes from 8 mice per group were counted on renal tissue sections stained for Ly-6G and presented as meanΒ±SEM. * p<0.05.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2570789&req=5

pone-0003596-g003: Renal influx of granulocytes in wild type and TLR4βˆ’/βˆ’ mice.Influx of granulocytes in kidneys from wild type (white bars) and TLR4βˆ’/βˆ’ (black bars) kidneys 1, 5 and 10 days after renal I/R injury or sham operation. One and ten days after I/R injury the number of granulocytes was significantly lower in kidneys of TLR4βˆ’/βˆ’ mice than in kidneys of wild type mice as counted in 10 randomly selected high-power fields (HPFs) on outer medulla (magnification Γ—400). The amount of granulocytes from 8 mice per group were counted on renal tissue sections stained for Ly-6G and presented as meanΒ±SEM. * p<0.05.
Mentions: In order to obtain insight into the role of TLR4 in renal inflammation, we compared granulocyte and macrophage influx in kidneys of TLR4βˆ’/βˆ’ and wild type mice by immunohistochemistry. Kidneys of wild type mice showed a transient increase in granulocyte influx with a peak one day after I/R injury (figure 3). Interestingly, TLR4βˆ’/βˆ’ kidneys showed significantly lower amounts of infiltrated granulocytes one and ten days after I/R injury compared with wild type kidneys. Analysis of macrophage influx revealed that there was an increased infiltration of these cells in the corticomedullary region with a peak ten days after I/R injury in kidneys which was similar in both TLR4βˆ’/βˆ’ and wild type mice (3.020Β±0.862 vs. 3.240Β±0.600 percentage staining/HPF).

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