Kuppfer Cells Trigger Nonalcoholic Steatohepatitis Development in Diet-induced Mouse Model through Tumor Necrosis Factor-α Production
Kuppfer Cells Trigger Nonalcoholic Steatohepatitis Development in Diet-induced Mouse Model through Tumor Necrosis Factor-α Production
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DOI：
10.1074/jbc.m112.417014
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发表时间：
2012-11-23
影响因子：
4.8
通讯作者：
Hahn, Young S.
中科院分区：
文献类型：
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作者：
Tosello-Trampont, Annie-Carole;Landes, Susan G.;Hahn, Young S.
非酒精性脂肪性肝炎 (NASH) 的特征是肝细胞内脂质沉积（脂肪变性），与肝损伤和炎症相关，并导致纤维化、肝硬化和肝癌的发展。然而，NASH的发病机制尚不清楚。为了确定不同的先天性骨髓亚群在 NASH 发展中的作用，我们检查了肝脏驻留巨噬细胞（即库普弗细胞）和血源性单核细胞在引发肝脏炎症和肝损伤中的作用。通过采用 NASH 小鼠模型，我们发现了 TNF α 和 Kupffer 细胞在 NASH 发生和进展中的先前未被认识到的作用。库普弗细胞的连续消耗降低了肝损伤、脂肪变性和促炎性单核细胞浸润的发生率。此外，我们的数据显示库普弗细胞和血单核细胞在 NASH 发展过程中的不同贡献；开始蛋氨酸/胆碱缺乏（MCD）饮食后2天和10天，库普弗细胞增加了TNFα的产生，随后CD11b(int)Ly6C(hi)单核细胞浸润。重要的是，定向敲低骨髓细胞中 TNF α 的表达可通过减少脂肪变性、肝损伤、单核细胞浸润和炎症趋化因子的产生来降低 NASH 的发生率。我们的研究结果表明，肝脏中产生 TNF α 的库普弗细胞的增加通过产生 TNF α 和 MCP-1 促进血液单核细胞浸润，对于 NASH 发展的早期阶段至关重要。
Nonalcoholic steatohepatitis (NASH), characterized by lipid deposits within hepatocytes (steatosis), is associated with hepatic injury and inflammation and leads to the development of fibrosis, cirrhosis, and hepatocarcinoma. However, the pathogenic mechanism of NASH is not well understood. To determine the role of distinct innate myeloid subsets in the development of NASH, we examined the contribution of liver resident macrophages (i.e. Kupffer cells) and blood-derived monocytes in triggering liver inflammation and hepatic damage. Employing a murine model of NASH, we discovered a previously unappreciated role for TNF alpha and Kupffer cells in the initiation and progression of NASH. Sequential depletion of Kupffer cells reduced the incidence of liver injury, steatosis, and proinflammatory monocyte infiltration. Furthermore, our data show a differential contribution of Kupffer cells and blood monocytes during the development of NASH; Kupffer cells increased their production of TNF alpha, followed by infiltration of CD11b(int)Ly6C(hi) monocytes, 2 and 10 days, respectively, after starting the methionine/choline- deficient (MCD) diet. Importantly, targeted knockdown of TNF alpha expression in myeloid cells decreased the incidence of NASH development by decreasing steatosis, liver damage, monocyte infiltration, and the production of inflammatory chemokines. Our findings suggest that the increase of TNF alpha-producing Kupffer cells in the liver is crucial for the early phase of NASH development by promoting blood monocyte infiltration through the production of TNF alpha and MCP-1.