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
2009 Journal of Clinical Investigation  
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.
more » ... of CC chemokines by the broadspectrum 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 CCR1and 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 CCR5deficient 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. Conflict of interest: The authors have declared that no conflict of interest exists. Nonstandard abbreviations used: Ad35k, adenovirus expressing the soluble broadspectrum CC chemokine inhibitor 35k; BDL, bile duct ligation; BMT, BM transplantation; HSC, hepatic stellate cell; RFP, red fluorescent protein. Citation for this article:
doi:10.1172/jci37444 fatcat:bfs5ranwjnalnm7qtfp653nxey