Renal-associated TLR2 mediates ischemia/reperfusion injury in the kidney

TLRs are conserved pattern recognition receptors that detect motifs of pathogens and host material released during injury. For unknown reasons, renal TLR2 mRNA is mainly expressed by tubular cells and is enhanced upon renal ischemia/reperfusion (I/R) injury. We evaluated the role of TLR2 in I/R inju...

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Veröffentlicht in:The Journal of clinical investigation Jg. 115; H. 10; S. 2894 - 2903
Hauptverfasser: Leemans, Jaklien C., Stokman, Geurt, Claessen, Nike, Rouschop, Kasper M., Teske, Gwendoline J.D., Kirschning, Carsten J., Akira, Shizuo, van der Poll, Tom, Weening, Jan J., Florquin, Sandrine
Format: Journal Article
Sprache:Englisch
Veröffentlicht: United States American Society for Clinical Investigation 01.10.2005
Schlagworte:
Adaptive immunity
Animals
Antigens
Biomedical research
Cells, Cultured
Chemokines
Chemokines - immunology
Chimera - genetics
Chimera - immunology
Cytokines
Inflammation
Inflammation - genetics
Inflammation - immunology
Inflammation - pathology
Inflammation - prevention & control
Ischemia
Kidney Diseases - genetics
Kidney Diseases - immunology
Kidney Diseases - pathology
Kidney Diseases - prevention & control
Kidney Tubules - immunology
Kidney Tubules - pathology
Kidneys
Leukocytes
Leukocytes - immunology
Male
Mice
Mice, Knockout
Oligodeoxyribonucleotides, Antisense - immunology
Oligodeoxyribonucleotides, Antisense - pharmacology
Oligodeoxyribonucleotides, Antisense - therapeutic use
Pathogens
Proteins
Reperfusion Injury - genetics
Reperfusion Injury - immunology
Reperfusion Injury - pathology
Reperfusion Injury - prevention & control
Toll-Like Receptor 2 - genetics
Toll-Like Receptor 2 - immunology
ISSN:0021-9738, 1558-8238
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Zusammenfassung:TLRs are conserved pattern recognition receptors that detect motifs of pathogens and host material released during injury. For unknown reasons, renal TLR2 mRNA is mainly expressed by tubular cells and is enhanced upon renal ischemia/reperfusion (I/R) injury. We evaluated the role of TLR2 in I/R injury using TLR2-/- and TLR2+/+ mice, TLR2 antisense oligonucleotides, and chimeric mice deficient in leukocyte or renal TLR2. Tubular cells needed TLR2 to produce significant cytokine and chemokine amounts upon ischemia in vitro. TLR2 played a proinflammatory and detrimental role in vivo after I/R injury, as reflected by a reduction in the amount of local cytokines and chemokines, leukocytes, and the level of renal injury and dysfunction in TLR2-/- mice compared with controls. Analysis of chimeric mice suggested that TLR2 expressed on renal parenchyma plays a crucial role in the induction of inflammation and injury. TLR2-antisense treatment protected mice from renal dysfunction, neutrophil influx, and tubular apoptosis after I/R injury compared with nonsense treatment. In summary, we identified renal-associated TLR2 as an important initiator of inflammatory responses leading to renal injury and dysfunction in I/R injury. These data imply that TLR2 blockade could provide a basis for therapeutic strategies to treat or prevent renal ischemic injury.
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Address correspondence to: Jaklien C. Leemans, Academic Medical Center, Meibergdreef 9, M2-108, 1105 AZ Amsterdam, The Netherlands. Phone: 31-20-5664240; Fax: 31-20-6960389; E-mail: j.c.leemans@amc.uva.nl.
ISSN:0021-9738
1558-8238
DOI:10.1172/JCI22832