Abstract
Hepatic injury is associated with a defective intestinal barrier and increased hepatic exposure to bacterial products. Here we report that the intestinal bacterial microflora and a functional Toll-like receptor 4 (TLR4), but not TLR2, are required for hepatic fibrogenesis. Using Tlr4-chimeric mice and in vivo lipopolysaccharide (LPS) challenge, we demonstrate that quiescent hepatic stellate cells (HSCs), the main precursors for myofibroblasts in the liver, are the predominant target through which TLR4 ligands promote fibrogenesis. In quiescent HSCs, TLR4 activation not only upregulates chemokine secretion and induces chemotaxis of Kupffer cells, but also downregulates the transforming growth factor (TGF)-β pseudoreceptor Bambi to sensitize HSCs to TGF-β–induced signals and allow for unrestricted activation by Kupffer cells. LPS-induced Bambi downregulation and sensitization to TGF-β is mediated by a MyD88–NF-κB–dependent pathway. Accordingly, Myd88-deficient mice have decreased hepatic fibrosis. Thus, modulation of TGF-β signaling by a TLR4-MyD88–NF-κB axis provides a novel link between proinflammatory and profibrogenic signals.
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Acknowledgements
The authors thank S. Akira (Osaka University, Osaka, Japan) for providing MyD88-deficient mice, J. Massague (Memorial Sloan-Kettering Cancer Center, New York, NY, USA) for providing dominant-negative Bambi plasmid, T. Akiyama (University of Tokyo, Tokyo, Japan) for providing Bambi-reporter plasmid, Y. Zhang for assistance with microarray analysis and A. Mencin (Columbia University, New York, New York, USA) for assistance with mouse studies. This study was supported by a Research Scholar Award from the American Gastroenterological Association (to R.F.S.), grants from the Uehara Memorial Foundation and the American Liver Foundation (to E.S.), an Alimenti e Salute grant from the University of Ancona (to S.D.M.), US National Institutes of Health grant R01GM041804 (to D.A.B.) and the Austrian Science Foundation (to C.H.Ö.).
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E.S. performed animal surgery and fibrosis evaluation, cell isolations, cell-culture studies, reporter assays and real-time PCR, generated recombinant adenoviruses, created figures and contributed to the design of the study and the writing of the manuscript. S.D.M. performed cell isolations, real-time PCR and microarray studies. Y.O. generated recombinant adenoviruses. C.H.Ö. generated recombinant adenoviruses. J.K. performed animal surgeries and cell isolations, performed western blots and assisted in fibrosis evaluation and in manuscript preparation. D.A.B. contributed to the design of the study, experimental design and the writing of the manuscript. R.F.S. (the principal investigator) designed and coordinated the study, contributed to experimental setup, data analysis and interpretation, and drafted and edited the manuscript.
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Supplementary Methods, Supplementary Figs. 1–6, Supplementart Table 1 (PDF 1452 kb)
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Seki, E., De Minicis, S., Österreicher, C. et al. TLR4 enhances TGF-β signaling and hepatic fibrosis. Nat Med 13, 1324–1332 (2007). https://doi.org/10.1038/nm1663
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DOI: https://doi.org/10.1038/nm1663