Limits...
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.

Show MeSH

Related in: MedlinePlus

Renal function, injury and inflammatory influx in wild type, MyD88−/− and TRIF-mutant mice.Renal function of MyD88−/− and TRIF-mutant mice (black bars) did not differ compared with that of their wild type mice (white bars) one day after renal I/R as reflected by serum urea (A) and creatinine (B) levels and tubular injury (C). In addition, no differences were observed in the number of infiltrating granulocytes in kidneys of MyD88−/− and TRIF-mutant mice compared with their wild type mice (D). Data are mean±SEM of 6 (TRIF) or 8 (MyD88) mice per group (sham-operated animals: n = 2/group (TRIF) or n = 3/group (MyD88)). * p<0.05.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2570789&req=5

pone-0003596-g008: Renal function, injury and inflammatory influx in wild type, MyD88−/− and TRIF-mutant mice.Renal function of MyD88−/− and TRIF-mutant mice (black bars) did not differ compared with that of their wild type mice (white bars) one day after renal I/R as reflected by serum urea (A) and creatinine (B) levels and tubular injury (C). In addition, no differences were observed in the number of infiltrating granulocytes in kidneys of MyD88−/− and TRIF-mutant mice compared with their wild type mice (D). Data are mean±SEM of 6 (TRIF) or 8 (MyD88) mice per group (sham-operated animals: n = 2/group (TRIF) or n = 3/group (MyD88)). * p<0.05.

Mentions: After having established that TLR4 plays a key role in initiating a proinflammatory response affecting renal function after I/R induction, we were interested in the relative contribution of the two separate downstream signaling cascades of TLR4 in renal I/R injury, one that relies on MyD88, and one that is mediated by TRIF. Since the differences in renal function, injury and granulocyte influx between TLR4−/− and wild type mice was most evident one day after I/R injury, further experiments were carried out at this time point. MyD88−/− mice showed a tendency towards decreased plasma urea and creatinine levels compared with wild type mice (figure 8a+b). However, these differences did not reach statistical significance. To verify these data, we performed an independent experiment with wild type and MyD88−/− mice and again did not find a significant difference in renal function (51.63±8.33 vs. 47.42±3.88 mmol/l ureum and 126.00±29.51 vs. 151.42±15.34 µmol/l creatinine) between both groups one day after I/R injury. The TRIF-mutant mice also did not show any differences in urea and creatinine levels compared with wild types (figure 8a+b). Moreover, no differences were observed in tubular damage between MyD88−/− and wild type mice (4.57±0.14 vs. 4.71±0.07) or TRIF-mutant and their wild type mice (3.90±0.52 vs. 3.34±0.56) after I/R injury (figure 8c). In line with renal function and histology, there were also no differences in granulocyte influx between MyD88−/− and TRIF-mutant mice compared with their wild types one day after I/R injury (figure 8d).


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 function, injury and inflammatory influx in wild type, MyD88−/− and TRIF-mutant mice.Renal function of MyD88−/− and TRIF-mutant mice (black bars) did not differ compared with that of their wild type mice (white bars) one day after renal I/R as reflected by serum urea (A) and creatinine (B) levels and tubular injury (C). In addition, no differences were observed in the number of infiltrating granulocytes in kidneys of MyD88−/− and TRIF-mutant mice compared with their wild type mice (D). Data are mean±SEM of 6 (TRIF) or 8 (MyD88) mice per group (sham-operated animals: n = 2/group (TRIF) or n = 3/group (MyD88)). * p<0.05.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0003596-g008: Renal function, injury and inflammatory influx in wild type, MyD88−/− and TRIF-mutant mice.Renal function of MyD88−/− and TRIF-mutant mice (black bars) did not differ compared with that of their wild type mice (white bars) one day after renal I/R as reflected by serum urea (A) and creatinine (B) levels and tubular injury (C). In addition, no differences were observed in the number of infiltrating granulocytes in kidneys of MyD88−/− and TRIF-mutant mice compared with their wild type mice (D). Data are mean±SEM of 6 (TRIF) or 8 (MyD88) mice per group (sham-operated animals: n = 2/group (TRIF) or n = 3/group (MyD88)). * p<0.05.
Mentions: After having established that TLR4 plays a key role in initiating a proinflammatory response affecting renal function after I/R induction, we were interested in the relative contribution of the two separate downstream signaling cascades of TLR4 in renal I/R injury, one that relies on MyD88, and one that is mediated by TRIF. Since the differences in renal function, injury and granulocyte influx between TLR4−/− and wild type mice was most evident one day after I/R injury, further experiments were carried out at this time point. MyD88−/− mice showed a tendency towards decreased plasma urea and creatinine levels compared with wild type mice (figure 8a+b). However, these differences did not reach statistical significance. To verify these data, we performed an independent experiment with wild type and MyD88−/− mice and again did not find a significant difference in renal function (51.63±8.33 vs. 47.42±3.88 mmol/l ureum and 126.00±29.51 vs. 151.42±15.34 µmol/l creatinine) between both groups one day after I/R injury. The TRIF-mutant mice also did not show any differences in urea and creatinine levels compared with wild types (figure 8a+b). Moreover, no differences were observed in tubular damage between MyD88−/− and wild type mice (4.57±0.14 vs. 4.71±0.07) or TRIF-mutant and their wild type mice (3.90±0.52 vs. 3.34±0.56) after I/R injury (figure 8c). In line with renal function and histology, there were also no differences in granulocyte influx between MyD88−/− and TRIF-mutant mice compared with their wild types one day after I/R injury (figure 8d).

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