title: Donor Toll-like receptor 4 contributes to ischemia and reperfusion injury following human kidney transplantation.
abstract: While studies in animal models have linked Toll-like receptor (TLR) 4 signaling to kidney injury induced by ischemia and reperfusion, the relevance of TLR4 activation to allograft injury in human kidney transplants is unknown. Here we show that TLR4 is constitutively expressed within all donor kidneys but is significantly higher in deceased-, compared with living-donor organs. Tubules from deceased- but not living-donor kidneys also stained positively for high-mobility group box-1 (HMGB1), a known endogenous TLR4 ligand. In vitro stimulation of human tubular cells with HMGB1, in a TLR4-dependent system, confirmed that HMGB1 can stimulate proinflammatory responses through TLR4. To assess the functional significance of TLR4 in human kidney transplantation, we determined whether TLR4 mutations that confer diminished affinity for HMGB1 influence intragraft gene-expression profiles and immediate graft function. Compared with kidneys expressing WT alleles, kidneys with a TLR4 loss-of-function allele contained less TNFalpha, MCP-1, and more heme oxygenase 1 (HO-1), and exhibited a higher rate of immediate graft function. These results represent previously undetected evidence that donor TLR4 contributes to graft inflammation and sterile injury following cold preservation and transplantation in humans. Targeting TLR4 signaling may have value in preventing or treating postischemic acute kidney injury after transplantation.
authors.affiliation: Division of Nephrology and Transplantion Institute, Mount Sinai School of Medicine, New York, NY 10029, USA.
authors.forename: Bernd
authors.initials: B
authors.lastname: Krüger
authors.forename: Stefanie
authors.initials: S
authors.lastname: Krick
authors.forename: Navdeep
authors.initials: N
authors.lastname: Dhillon
authors.forename: Susan M
authors.initials: SM
authors.lastname: Lerner
authors.forename: Scott
authors.initials: S
authors.lastname: Ames
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Bromberg
authors.forename: Marvin
authors.initials: M
authors.lastname: Lin
authors.forename: Liron
authors.initials: L
authors.lastname: Walsh
authors.forename: John
authors.initials: J
authors.lastname: Vella
authors.forename: Michael
authors.initials: M
authors.lastname: Fischereder
authors.forename: Bernhard K
authors.initials: BK
authors.lastname: Krämer
authors.forename: Robert B
authors.initials: RB
authors.lastname: Colvin
authors.forename: Peter S
authors.initials: PS
authors.lastname: Heeger
authors.forename: Barbara T
authors.initials: BT
authors.lastname: Murphy
authors.forename: Bernd
authors.initials: B
authors.lastname: Schröppel
mesh_terms: D001706:Biopsy; D005786:Gene Expression Regulation; D006085:Graft Survival; D024243:HMGB1 Protein / Q000378:metabolism; D006801:Humans; D016030:Kidney Transplantation / Q000379:methods*; D009154:Mutation / Q000235:genetics; D011485:Protein Binding; D015427:Reperfusion Injury / Q000378:metabolism*; D014019:Tissue Donors; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D024243:HMGB1 Protein; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4