Hepatic macrophages but not dendritic cells contribute to liver fibrosis by promoting the survival of activated hepatic stellate cells in mice

Authors


  • Potential conflict of interest: Nothing to report.

  • This study was supported by NIH grants R01DK076920 and U54CA163111 (both to Robert F. Schwabe). Jean-Philippe Pradere was supported by a postdoctoral fellowship from the American Liver Foundation. Johannes Kluwe was supported by the German Research Foundation (grant KL2140/2-1) and a Sheila Sherlock fellowship from the European Association for the Study of the Liver. Ingmar Mederacke was supported by the German Research Foundation (grant ME3723/1-1). Dianne Dapito was supported by NIH grant 1F31DK091980. Costica Aloman was supported by NIH grant 1K08DK088954.

Address reprint requests to: Robert F. Schwabe, Department of Medicine, Columbia University, College of Physicians & Surgeons, Russ Berrie Pavilion, Room 415, 1150 St. Nicholas Ave, New York, NY 10032; E-mail: rfs2102@columbia.edu; fax: 212-851-5461

Abstract

Although it is well established that hepatic macrophages play a crucial role in the development of liver fibrosis, the underlying mechanisms remain largely elusive. Moreover, it is not known whether other mononuclear phagocytes such as dendritic cells (DCs) contribute to hepatic stellate cell (HSC) activation and liver fibrosis. We show for the first time that hepatic macrophages enhance myofibroblast survival in a nuclear factor kappa B (NF-κB)–dependent manner and thereby promote liver fibrosis. Microarray and pathway analysis revealed no induction of HSC activation pathways by hepatic macrophages but a profound activation of the NF-κB pathway in HSCs. Conversely, depletion of mononuclear phagocytes during fibrogenesis in vivo resulted in suppressed NF-κB activation in HSCs. Macrophage-induced activation of NF-κB in HSCs in vitro and in vivo was mediated by interleukin (IL)−1 and tumor necrosis factor (TNF). Notably, IL-1 and TNF did not promote HSC activation but promoted survival of activated HSCs in vitro and in vivo and thereby increased liver fibrosis, as demonstrated by neutralization in coculture experiments and genetic ablation of IL-1 and TNF receptor in vivo. Coculture and in vivo ablation experiments revealed only a minor contribution to NF-κB activation in HSCs by DCs, and no contribution of DCs to liver fibrosis development, respectively. Conclusion: Promotion of NF-κB–dependent myofibroblast survival by macrophages but not DCs provides a novel link between inflammation and fibrosis. (Hepatology 2013;58:1461–1473)

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