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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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Levels of proinflammatory cytokines and chemokines in wild type and TLR4−/− mice.Expression of proinflammatory chemokines KC and MCP-1 in kidney homogenates of wild type (white bars) and TLR4−/− (black bars) mice one day after I/R injury or sham-operation. KC levels were significantly lower in homogenate of TLR4−/− kidneys compared with wild type kidneys, whereas there were no differences observed in MCP-1 levels. Data are mean±SEM of 8 mice per group measured in duplicate (sham-operated animals: n = 3/group). * p<0.05.
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pone-0003596-g004: Levels of proinflammatory cytokines and chemokines in wild type and TLR4−/− mice.Expression of proinflammatory chemokines KC and MCP-1 in kidney homogenates of wild type (white bars) and TLR4−/− (black bars) mice one day after I/R injury or sham-operation. KC levels were significantly lower in homogenate of TLR4−/− kidneys compared with wild type kidneys, whereas there were no differences observed in MCP-1 levels. Data are mean±SEM of 8 mice per group measured in duplicate (sham-operated animals: n = 3/group). * p<0.05.

Mentions: To evaluate whether early differences in the influx of granulocytes could be explained by differences in cytokine/chemokine production, we determined the concentrations of Keratinocyte Chemoattractant (KC) and Monocyte Chemoattractant-1 (MCP-1) in kidney homogenates of TLR4−/− and wild type mice one day after I/R injury. In accordance with the lower amount of granulocytes in the TLR4−/− kidneys, the levels of granulocyte chemoattractant KC were significantly reduced in the TLR4−/− kidney homogenates compared with that of wild type mice (figure 4). The levels of monocyte chemoattractant MCP-1 did not differ between kidney homogenates of TLR4−/− and wild type mice one day after 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)

Levels of proinflammatory cytokines and chemokines in wild type and TLR4−/− mice.Expression of proinflammatory chemokines KC and MCP-1 in kidney homogenates of wild type (white bars) and TLR4−/− (black bars) mice one day after I/R injury or sham-operation. KC levels were significantly lower in homogenate of TLR4−/− kidneys compared with wild type kidneys, whereas there were no differences observed in MCP-1 levels. Data are mean±SEM of 8 mice per group measured in duplicate (sham-operated animals: n = 3/group). * p<0.05.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0003596-g004: Levels of proinflammatory cytokines and chemokines in wild type and TLR4−/− mice.Expression of proinflammatory chemokines KC and MCP-1 in kidney homogenates of wild type (white bars) and TLR4−/− (black bars) mice one day after I/R injury or sham-operation. KC levels were significantly lower in homogenate of TLR4−/− kidneys compared with wild type kidneys, whereas there were no differences observed in MCP-1 levels. Data are mean±SEM of 8 mice per group measured in duplicate (sham-operated animals: n = 3/group). * p<0.05.
Mentions: To evaluate whether early differences in the influx of granulocytes could be explained by differences in cytokine/chemokine production, we determined the concentrations of Keratinocyte Chemoattractant (KC) and Monocyte Chemoattractant-1 (MCP-1) in kidney homogenates of TLR4−/− and wild type mice one day after I/R injury. In accordance with the lower amount of granulocytes in the TLR4−/− kidneys, the levels of granulocyte chemoattractant KC were significantly reduced in the TLR4−/− kidney homogenates compared with that of wild type mice (figure 4). The levels of monocyte chemoattractant MCP-1 did not differ between kidney homogenates of TLR4−/− and wild type mice one day after 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