CCR1 and CCR5 promote hepatic fibrosis in mice
Ekihiro Seki, Samuele De Minicis, Geum-Youn Gwak, Johannes Kluwe, Sayaka Inokuchi, Christina A. Bursill, Josep M. Llovet, David A. Brenner, Robert F. Schwabe
Ekihiro Seki, Samuele De Minicis, Geum-Youn Gwak, Johannes Kluwe, Sayaka Inokuchi, Christina A. Bursill, Josep M. Llovet, David A. Brenner, Robert F. Schwabe
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Research Article Hepatology

CCR1 and CCR5 promote hepatic fibrosis in mice

Abstract

Hepatic fibrosis develops as a response to chronic liver injury and almost exclusively occurs in a proinflammatory environment. However, the role of inflammatory mediators in fibrogenic responses of the liver is only poorly understood. We therefore investigated the role of CC chemokines and their receptors in hepatic fibrogenesis. The CC chemokines MIP-1α, MIP-1β, and RANTES and their receptors CCR1 and CCR5 were strongly upregulated in 2 experimental mouse models of fibrogenesis. Neutralization of CC chemokines by the broad-spectrum CC chemokine inhibitor 35k efficiently reduced hepatic fibrosis, and CCR1- and CCR5-deficient mice displayed substantially reduced hepatic fibrosis and macrophage infiltration. Analysis of fibrogenesis in CCR1- and CCR5-chimeric mice revealed that CCR1 mediates its profibrogenic effects in BM-derived cells, whereas CCR5 mediates its profibrogenic effects in resident liver cells. CCR5 promoted hepatic stellate cell (HSC) migration through a redox-sensitive, PI3K-dependent pathway. Both CCR5-deficient HSCs and CCR1- and CCR5-deficient Kupffer cells displayed strong suppression of CC chemokine–induced migration. Finally, we detected marked upregulation of RANTES, CCR1, and CCR5 in patients with hepatic cirrhosis, confirming activation of the CC chemokine system in human fibrogenesis. Our data therefore support a role for the CC chemokine system in hepatic fibrogenesis and suggest distinct roles for CCR1 and CCR5 in Kupffer cells and HSCs.

Authors

Ekihiro Seki, Samuele De Minicis, Geum-Youn Gwak, Johannes Kluwe, Sayaka Inokuchi, Christina A. Bursill, Josep M. Llovet, David A. Brenner, Robert F. Schwabe

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Figure 6

CCR1 and CCR5 promote biliary fibrosis through different cell populations.

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CCR1 and CCR5 promote biliary fibrosis through different cell population...
BMT was performed to generate wild-type mice with wild-type BM, wild-type mice with Ccr1–/– or Ccr5–/– BM, Ccr1–/– mice with wild-type or Ccr1–/– BM, and Ccr5–/– mice with wild-type or Ccr5–/– BM. (A) Successful BMT was tested by comparing splenic levels of Ccr1 and Ccr5 mRNA, which are expressed as fold change compared with wild-type mice transplanted with wild-type BM. ND, not detectable. (B–G) Mice underwent 3-week BDL 3 months after BMT. Hepatic fibrosis was evaluated by Sirius red staining (B and E; original magnification, ×100), quantification of the Sirius red–positive area (C and F), and hepatic hydroxyproline quantification (D and G). *P < 0.05, **P < 0.01.