Cutting edge: TLR4 activation mediates liver ischemia/reperfusion inflammatory response via IFN regulatory factor 3-dependent MyD88-independent pathway.
The triggering molecular mechanism of ischemia-reperfusion injury (IRI), which in clinical settings results in excessive and detrimental inflammatory responses, remains unclear. This study analyzes the role of the TLR system in an established murine model of liver warm ischemia followed by reperfusion. By contrasting in parallel TLR knockout mice with their wild-type counterparts, we found that TLR4, but not TLR2, was specifically required in initiating the IRI cascade, as manifested by liver function (serum alanine aminotransferase levels), pathology, and local induction of proinflammatory cytokines/chemokines (TNF-alpha, IL-6, IFN-inducible protein 10). We then investigated the downstream signaling pathway of TLR4 activation. Our results show that IFN regulatory factor 3, but not MyD88, mediated IRI-induced TLR4 activation leading to liver inflammation and hepatocellular damage. This study documents the selective usage of TLR in a clinically relevant noninfectious disease model, and identifies a triggering molecular mechanism in the pathophysiology of liver IRI.
Zhai
Yuan
Y
Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine, University of California, Los Angeles, USA.
Shen
Xiu-da
XD
O'Connell
Ryan
R
Gao
Feng
F
Lassman
Charles
C
Busuttil
Ronald W
RW
Cheng
Genhong
G
Kupiec-Weglinski
Jerzy W
JW
D048868:Adaptor Proteins, Signal Transducing; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D000943:Antigens, Differentiation / Q000502:physiology*; D018925:Chemokines / Q000096:biosynthesis / Q000235:genetics; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D004268:DNA-Binding Proteins / Q000502:physiology*; D005786:Gene Expression Regulation / Q000276:immunology; D018836:Inflammation Mediators / Q000378:metabolism / Q000502:physiology*; D050838:Interferon Regulatory Factor-3; D016899:Interferon-beta / Q000096:biosynthesis; D008099:Liver / Q000098:blood supply* / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88; D011956:Receptors, Cell Surface / Q000172:deficiency / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D011971:Receptors, Immunologic / Q000502:physiology*; D015427:Reperfusion Injury / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D014157:Transcription Factors / Q000502:physiology*
D048868:Adaptor Proteins, Signal Transducing; D000943:Antigens, Differentiation; D018925:Chemokines; D016207:Cytokines; D004268:DNA-Binding Proteins; D018836:Inflammation Mediators; D050838:Interferon Regulatory Factor-3; C494233:Irf3 protein, mouse; D008562:Membrane Glycoproteins; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D014157:Transcription Factors; D016899:Interferon-beta; D000410:Alanine Transaminase