4.8 Article

CCR1 and CCR5 promote hepatic fibrosis in mice

期刊

JOURNAL OF CLINICAL INVESTIGATION
卷 119, 期 7, 页码 1858-1870

出版社

AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI37444

关键词

-

资金

  1. American Liver Foundation
  2. NIH [1R01DK076920, SR01GM041804]
  3. Uehara Memorial Foundation
  4. Institucio Catatana de Recerca i Estudis Avanqats
  5. NIDDK [1R01DK076986-01]
  6. Samuel Waxman Cancer Research Foundation
  7. Spanish National Health Institute [SAF-2007-61898]

向作者/读者索取更多资源

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-1 alpha, MIP-1 beta, 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.

作者

我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。

评论

主要评分

4.8
评分不足

次要评分

新颖性
-
重要性
-
科学严谨性
-
评价这篇论文

推荐

暂无数据
暂无数据