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 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 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.

Migration of Fibrocytes in Fibrogenic Liver Injury

“…Recent studies have demonstrated that BDL-and CCl 4 -induced fibrosis is markedly reduced in CCR2 Ϫ/Ϫ , CCR1 Ϫ/Ϫ , and TLR4 Ϫ/Ϫ mice. [27][28][29] However, although BM chimeric mice exhibiting CCR2 Ϫ/Ϫ or CCR1 Ϫ/Ϫ BM demonstrated less macrophage and fibrocyte recruitment in response to liver injury, individual deficiency of CCR2 or CCR1 (or TLR4) in hematopoietic cells has little or no effect on extent of hepatic fibrosis.…”

An orally available small imidazolium salt ameliorates inflammation and fibrosis in a murine model of cholestasis

“…17 At the molecular level, specific genes contributing to inflammation were also implicated as mediators for fibrogenesis. 3,[18][19][20] Although the relationship between inflammation and fibrosis is not always straightforward due to the complex cross-talks among different cells types and pathways, reducing inflammation and immune response has been recognized as one of the major approaches to combat fibrosis. For example, the gene-based dominatenegative form of MCP-1 has been shown to suppress activated HSC and reduce liver fibrosis in rats.…”

Phenotypic Changes in Hepatic Stellate Cells in Response to Toxic Liver Injury

“…Chemokines, released at the site of injury, stimulate HSC migration by forming a chemotactic gradient. This process is similar to immune cell chemotaxis, and many of the chemokines that stimulate migration of immune cells also stimulate HSC chemotaxis, such as MIP-1a, MIP-1b, RANTES, and MCP-1 [41][42][43]. In addition to these traditional chemokines, various growth factors, such as VEGF and PDGF, and the protein osteopontin stimulate HSC chemotaxis [44][45][46].…”

“…HSCs express the traditional chemokine receptors, Ccr2 and Ccr5, which are activated by MIP-1a, MIP-1b, RAN-TES, and MCP-1 [42,43]. In vitro, HSCs migrate toward these chemokines in a Ccr2-or Ccr5-dependent mechanism, and in vivo, liver fibrosis is reduced in Ccr2 and Ccr5 knockout mice [42,43].…”

“…In vitro, HSCs migrate toward these chemokines in a Ccr2-or Ccr5-dependent mechanism, and in vivo, liver fibrosis is reduced in Ccr2 and Ccr5 knockout mice [42,43]. To distinguish between the role of these receptors on immune cells and non-immune cells, bone marrow from wild-type mice was transplanted into Ccr2 and Ccr5 knockout mice in these studies.…”