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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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Related in: MedlinePlus

In vitro production of proinflammatory cytokines and chemokines by wild type and TLR4−/− TECs.Production of proinflammatory cytokines and chemokines by primary murine TECs from TLR4−/− (black) and wild type (white) mice, subjected to simulated ischemia. TLR4−/− TECs produce significantly lower amounts of KC as compared with TECs from wild type mice when subjected to simulated ischemia, whereas levels of MCP-1 were similar. Data are mean±SEM of 4–5 mice per group, measured in duplicate. * p<0.05. Ctr, control; Isch, Ischemia.
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pone-0003596-g005: In vitro production of proinflammatory cytokines and chemokines by wild type and TLR4−/− TECs.Production of proinflammatory cytokines and chemokines by primary murine TECs from TLR4−/− (black) and wild type (white) mice, subjected to simulated ischemia. TLR4−/− TECs produce significantly lower amounts of KC as compared with TECs from wild type mice when subjected to simulated ischemia, whereas levels of MCP-1 were similar. Data are mean±SEM of 4–5 mice per group, measured in duplicate. * p<0.05. Ctr, control; Isch, Ischemia.

Mentions: To evaluate whether renal epithelium can contribute to the initiation of an inflammatory response upon I/R injury in a TLR4-dependent manner, cultured primary tubular epithelial cells from TLR4−/− and wild type kidneys were subjected to simulated ischemia, and cytokine/chemokine levels were subsequently measured in the supernatant. As shown in figure 5, levels of KC were significantly lower whereas levels of MCP-1 were similar in the supernatant of TLR4−/− TECs compared with wild type TECs when subjected to simulated ischemia. The levels of TNF-α were below detection level. These data show that TLR4 on epithelial cells can indeed contribute to the induction of proinflammatory responses upon ischemic injury in vitro.


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)

In vitro production of proinflammatory cytokines and chemokines by wild type and TLR4−/− TECs.Production of proinflammatory cytokines and chemokines by primary murine TECs from TLR4−/− (black) and wild type (white) mice, subjected to simulated ischemia. TLR4−/− TECs produce significantly lower amounts of KC as compared with TECs from wild type mice when subjected to simulated ischemia, whereas levels of MCP-1 were similar. Data are mean±SEM of 4–5 mice per group, measured in duplicate. * p<0.05. Ctr, control; Isch, Ischemia.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0003596-g005: In vitro production of proinflammatory cytokines and chemokines by wild type and TLR4−/− TECs.Production of proinflammatory cytokines and chemokines by primary murine TECs from TLR4−/− (black) and wild type (white) mice, subjected to simulated ischemia. TLR4−/− TECs produce significantly lower amounts of KC as compared with TECs from wild type mice when subjected to simulated ischemia, whereas levels of MCP-1 were similar. Data are mean±SEM of 4–5 mice per group, measured in duplicate. * p<0.05. Ctr, control; Isch, Ischemia.
Mentions: To evaluate whether renal epithelium can contribute to the initiation of an inflammatory response upon I/R injury in a TLR4-dependent manner, cultured primary tubular epithelial cells from TLR4−/− and wild type kidneys were subjected to simulated ischemia, and cytokine/chemokine levels were subsequently measured in the supernatant. As shown in figure 5, levels of KC were significantly lower whereas levels of MCP-1 were similar in the supernatant of TLR4−/− TECs compared with wild type TECs when subjected to simulated ischemia. The levels of TNF-α were below detection level. These data show that TLR4 on epithelial cells can indeed contribute to the induction of proinflammatory responses upon ischemic injury in vitro.

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