title: TLR2 is constitutively expressed within the kidney and participates in ischemic renal injury through both MyD88-dependent and -independent pathways.
abstract: TLRs are an evolutionarily conserved family of cell membrane proteins believed to play a significant role in innate immunity and the response to tissue injury, including that induced by ischemia. TLR signaling pathways activate transcription factors that regulate expression of prosurvival proteins, as well as proinflammatory cytokines and chemokines through one of two proximal adapter proteins, MyD88 or Toll/IL-1R domain-containing adaptor-inducing IFN-beta (Trif). Our study defines the constitutive protein expression of TLR2 in kidneys of humans and mice, and provides insight into the signaling mechanisms by which a deficiency of TLR2 protects from ischemic organ injury. Our study compared and contrasted the effects of renal ischemia in wild-type mice and mice deficient in TLR2, MyD88, Trif, and MyD88xTrif. TLR2 protein was evident in many cell types in the kidney, including renal tubules of the outer stripe of the medulla, glomeruli, and in the renal vasculature. The pattern of protein expression was similar in humans and mice. The absence of TLR2, MyD88, and MyD88xTrif conferred both physiologic and histologic protection against sublethal ischemia at 24 h. Interestingly, TLR2-deficient mice were better protected from ischemic renal injury than those deficient for the adapter protein MyD88, raising the intriguing possibility that TLR-2-dependent/MyD88-independent pathways also contribute to kidney injury. We conclude that TLR2 protein is constitutively expressed in the kidney and plays an important role in the pathogenesis of acute ischemic injury by signaling both MyD88-dependent and MyD88-independent pathways.
authors.affiliation: Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Alana A
authors.initials: AA
authors.lastname: Shigeoka
authors.forename: Todd D
authors.initials: TD
authors.lastname: Holscher
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: King
authors.forename: Frank W
authors.initials: FW
authors.lastname: Hall
authors.forename: William B
authors.initials: WB
authors.lastname: Kiosses
authors.forename: Peter S
authors.initials: PS
authors.lastname: Tobias
authors.forename: Nigel
authors.initials: N
authors.lastname: Mackman
authors.forename: Dianne B
authors.initials: DB
authors.lastname: McKay
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000172:deficiency / Q000235:genetics; D000818:Animals; D006801:Humans; D007668:Kidney / Q000276:immunology* / Q000378:metabolism; D007674:Kidney Diseases / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000502:physiology*; D015427:Reperfusion Injury / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000235:genetics* / Q000276:immunology*; D051195:Toll-Like Receptor 2 / Q000096:biosynthesis* / Q000235:genetics* / Q000502:physiology
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D053594:Myeloid Differentiation Factor 88; D051195:Toll-Like Receptor 2; C507780:Myd88 protein, mouse; C476286:Ticam1 protein, mouse; C493486:Tlr2 protein, mouse