Donor Toll-like receptor 4 contributes to ischemia and reperfusion injury following human kidney transplantation

被引:271
作者
Krueger, Bernd [1 ,5 ]
Krick, Stefanie [1 ]
Dhillon, Navdeep [1 ]
Lerner, Susan M. [2 ]
Ames, Scott [2 ]
Bromberg, Jonathan S. [2 ]
Lin, Marvin [1 ]
Walsh, Liron [1 ]
Vella, John [3 ]
Fischereder, Michael [4 ]
Kraemer, Bernhard K. [5 ]
Colvin, Robert B. [6 ]
Heeger, Peter S. [1 ,2 ]
Murphy, Barbara T. [1 ,2 ]
Schroeppel, Bernd [1 ,2 ]
机构
[1] Mt Sinai Sch Med, Div Nephrol, New York, NY 10029 USA
[2] Mt Sinai Sch Med, Inst Transplantat, New York, NY 10029 USA
[3] Maine Med Ctr, Div Nephrol, Portland, ME 04102 USA
[4] Univ Munich, Med Poliklin Innenstadt Munchen, Munich, Germany
[5] Klinikum Ruhr Univ Bochum, Med Klin 1, Marienhosp Herne, Bochum, Germany
[6] Pathol Res Massachusetts Gen Hosp, Boston, MA 02114 USA
基金
美国国家卫生研究院;
关键词
delayed graft function; high mobility group box-1; DELAYED GRAFT FUNCTION; RENAL-TRANSPLANTATION; ISCHEMIA/REPERFUSION INJURY; LIVER ISCHEMIA; IMMUNE-SYSTEM; TLR4; TOLL-LIKE-RECEPTOR-4; POLYMORPHISMS; INFLAMMATION; PROTEIN;
D O I
10.1073/pnas.0810169106
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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 TNF alpha, 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.
引用
收藏
页码:3390 / 3395
页数:6
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