Premium
C‐C motif chemokine receptor 9 positive macrophages activate hepatic stellate cells and promote liver fibrosis in mice
Author(s) -
Chu Posung,
Nakamoto Nobuhiro,
Ebinuma Hirotoshi,
Usui Shingo,
Saeki Keita,
Matsumoto Atsuhiro,
Mikami Yohei,
Sugiyama Kazuo,
Tomita Kengo,
Kanai Takanori,
Saito Hidetsugu,
Hibi Toshifumi
Publication year - 2013
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.26351
Subject(s) - hepatic stellate cell , chemokine , liver fibrosis , ccl25 , fibrosis , ccr2 , chemistry , chemokine receptor , c c chemokine receptor type 6 , receptor , microbiology and biotechnology , medicine , pathology , biology , biochemistry
Chemokine receptors mediate migration of immune cells into the liver, thereby promoting liver inflammation. C‐C motif chemokine receptor (CCR) 9 + macrophages are crucial in the pathogenesis of acute liver inflammation, but the role and underlying mechanisms of this macrophage subset in chronic liver injury and subsequent liver fibrosis are not fully understood. We confirmed that tumor necrosis factor alpha (TNF‐α)‐producing CCR9 + macrophages accumulated during the initiation of carbon tetrachloride (CCl 4 )‐induced liver injury, and CCR9 deficiency attenuated the degree of liver damage. Accumulation of CCR9 + macrophages persisted prominently during the process of liver fibrosis induced by repetitive CCl 4 or thioacetamide (TAA)/leptin administration. Increased CCR9 expression was also found on activated hepatic stellate cells (HSCs). Importantly, experimental liver fibrosis was significantly ameliorated in CCR9 −/− mice compared with wild‐type (WT) mice, assessed by α‐smooth muscle actin (α‐SMA) immunostain, Sirius red staining, and messenger RNA (mRNA) expression levels of α‐ SMA, collagen 1α1, transforming growth factor (TGF)‐β1 , and tissue inhibitor of metalloproteinase (TIMP)‐1 . Accumulated CD11b + macrophages in CCl 4 ‐treated WT mice showed marked increases in TNF, NO synthase‐2 , and TGF‐β1 mRNA expression compared with CCR9 −/− mice, implying proinflammatory and profibrogenic properties. Hepatic CD11b + macrophages from CCl 4 ‐treated WT mice (i.e., CCR9 + macrophages), but not CD8 + T lymphocytes or non‐CD11b + cells, significantly activated HSCs in vitro compared with those from CCR9 −/− mice. TNF‐α or TGF‐β1 antagonism attenuated CCR9 + macrophage‐induced HSC activation. Furthermore, C‐C motif chemokine ligand (CCL) 25 mediated migration and, to a lesser extent, activation of HSCs in vitro . Conclusion : Accumulated CD11b + macrophages are critical for activating HSCs through the CCR9/CCL25 axis and therefore promote liver fibrosis. CCR9 antagonism might be a novel therapeutic target for liver fibrosis. (H EPATOLOGY 2013;)