Hepatic Recruitment of the Inflammatory Gr1+ Monocyte Subset Upon Liver Injury Promotes Hepatic Fibrosis
Hepatic Recruitment of the Inflammatory Gr1+ Monocyte Subset Upon Liver Injury Promotes Hepatic Fibrosis
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DOI：
10.1002/hep.22950
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发表时间：
2009-07-01
期刊：
影响因子：
13.5
通讯作者：
Tacke, Frank
中科院分区：
文献类型：
--
作者：
Karlmark, Karlin Raja;Weiskirchen, Ralf;Tacke, Frank
除了肝脏驻留的枯否细胞外，浸润的免疫细胞最近与肝纤维化的发展有关。血液单核细胞是组织巨噬细胞的循环前体;在小鼠中可分为两个功能不同的亚群：Gr 1（hi）（Ly 6C（hi））和Gr 1（lo）（Ly 6C（lo））单核细胞。这些单核细胞亚群在肝纤维化中的作用以及它们分化募集到受损肝脏中的机制尚不清楚。因此，我们采用流式细胞术和免疫组化技术，对急性和慢性四氯化碳（CCl 4）诱导的小鼠肝损伤中浸润单核细胞的亚群进行了表征。在毒性损伤后，炎症性Gr 1（hi）单核细胞（而非Gr 1（lo）单核细胞）被大量募集到肝脏中，导致CD 11b（+）F4/80（+）肝内巨噬细胞增加高达10倍。将野生型小鼠与C-C趋化因子受体（CCR 2）缺陷小鼠和CCR 2/CCR 6缺陷小鼠进行比较，发现CCR 2通过介导单核细胞从骨髓中排出来严格控制肝内Gr 1（hi）单核细胞积聚。在慢性肝损伤期间，肝内CD 11b（+）F4/80（+）Gr 1（+）单核细胞来源的细胞优先分化为产生诱导型一氧化氮合酶的巨噬细胞，发挥促炎和促纤维化作用，例如促进肝星状细胞（HSC）活化、T辅助细胞1-T细胞分化和转化生长因子β（TGF-β）释放。Ccr 2（-/-）和Ccr 2（-/-）Ccr 6（-/-）小鼠中受损的单核细胞亚群募集导致HSC活化减少和肝纤维化减轻。此外，过继转移的Gr 1（hi）单核细胞进入受损的肝脏，并促进野生型和Ccr 2（-/-）Ccr 6（-/-）小鼠的纤维化进展，这些小鼠在其他方面受到保护免于肝纤维化。从CCl 4处理的动物中纯化的肝内CD 11b（+）F4/80（+）Gr 1（+）单核细胞衍生的巨噬细胞，而不是幼稚骨髓单核细胞或对照淋巴细胞，在体外以TGF-β依赖的方式直接激活HSC。结论：炎症性Gr 1（+）单核细胞通过CCR 2依赖性骨髓排出被招募到损伤的肝脏中，促进肝纤维化的进展。因此，它们可能是抗纤维化策略的一个有趣的新靶点。（《肝脏病学》2009年;50：261-274）
In addition to liver-resident Kupffer cells, infiltrating immune cells have recently been linked to the development of liver fibrosis. Blood monocytes are circulating precursors of tissue macrophages; and can be divided into two functionally distinct subpopulations in mice: Gr1(hi) (Ly6C(hi)) and Gr1(lo) (Ly6C(lo)) monocytes. The role of these monocyte subsets in hepatic fibrosis and the mechanisms of their differential recruitment into the injured liver are unknown. We therefore characterized subpopulations; of infiltrating monocytes in acute and chronic carbon tetrachloride (CCl4)-induced liver injury in mice using flow cytometry and immunohistochemistry. Inflammatory Gr1(hi) but not Gr1(lo) monocytes are massively recruited into the liver upon toxic injury constituting an up to 10-fold increase in CD11b(+)F4/80(+) intrahepatic macrophages. Comparing wild-type with C-C chemokine receptor (CCR2)-deficient and CCR2/CCR6-deficient mice revealed that CCR2 critically controls intrahepatic Gr1(hi) monocyte accumulation by mediating their egress from bone marrow. During chronic liver damage, intrahepatic CD11b(+)F4/80(+)Gr1(+) monocyte-derived cells differentiate preferentially into inducible nitric oxide synthase-producing macrophages exerting proinflammatory and profibrogenic actions, such as promoting hepatic stellate cell (HSC) activation, T helper 1-T cell differentiation and transforming growth factor beta (TGF-beta) release. Impaired monocyte subset recruitment in Ccr2(-/-) and Ccr2(-/-)Ccr6(-/-) mice results in reduced HSC activation and diminished liver fibrosis. Moreover, adoptively transferred Gr1(hi) monocytes traffic into the injured liver and promote fibrosis progression in wild-type and Ccr2(-/-)Ccr6(-/-) mice, which are otherwise protected from hepatic fibrosis. Intrahepatic CD11b(+)F4/80(+)Gr1(+) monocyte-derived macrophages purified from CCl4-treated animals, but not naive bone marrow monocytes or control lymphocytes, directly activate HSCs in a TGF-beta-dependent manner in vitro. Conclusion: Inflammatory Gr1(+) monocytes, recruited into the injured liver via CCR2-dependent bone marrow egress, promote the progression of liver fibrosis. Thus, they may represent an interesting novel target for antifibrotic strategies. (HEPATOLOGY 2009;50:261-274.)