Toll-like receptor-4 coordinates the innate immune response of the kidney to renal ischemia/reperfusion injury.
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.
Pulskens
Wilco P
WP
Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. w.p.pulskens@amc.uva.nl
Teske
Gwendoline J
GJ
Butter
Loes M
LM
Roelofs
Joris J
JJ
van der Poll
Tom
T
Florquin
Sandrine
S
Leemans
Jaklien C
JC
D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D049109:Cell Proliferation; D020022:Genetic Predisposition to Disease; D006098:Granulocytes / Q000276:immunology / Q000378:metabolism; D007113:Immunity, Innate / Q000235:genetics*; D007249:Inflammation / Q000235:genetics / Q000276:immunology; D007668:Kidney / Q000276:immunology* / Q000378:metabolism / Q000473:pathology / Q000502:physiology; D007674:Kidney Diseases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000503:physiopathology; D051379:Mice; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics; D020556:Neutrophil Infiltration / Q000235:genetics / Q000276:immunology; D015427:Reperfusion Injury / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000502:physiology*
D033942:Adaptor Proteins, Vesicular Transport; D053594:Myeloid Differentiation Factor 88; D051197:Toll-Like Receptor 4; C507780:Myd88 protein, mouse; C476286:Ticam1 protein, mouse; C493487:Tlr4 protein, mouse