炎症
内吞作用
癌症研究
免疫疗法
程序性细胞死亡
巨噬细胞
医学
免疫系统
髓样
免疫学
内体
生物
细胞凋亡
内科学
受体
生物化学
体外
作者
Dan Yang,Taikun Tian,Xiaojing Li,Baokai Zhang,Linlin Qi,Fan Zhang,Moonsik Han,Shuang Wang,Jun Xiao,Yingying Gou,Raorao Zhang,Qiaojie Liu,Shih Bin Su,Jiahui Liu,Xiaowu Huang,Qiang Gao,Lijian Hui,Huiru Tang,Hongyan Wang,Bin Wei
标识
DOI:10.1097/hep.0000000000000629
摘要
HCC is closely associated with inflammation and immune modulation, and combined chemotherapy with other strategies is under extensive investigation to achieve better efficacy. HCC is accompanied by zinc (Zn) deficiency. This study aims to understand how Zn could affect macrophage function and its application for HCC therapy.Zn 2+ and the Zn transporter 1 (ZNT1, solute carrier family 30 member 1) were markedly reduced in intrahepatic macrophages from patients with HCC and from mouse liver tumors. Lower ZNT1 expression was associated with higher IL-6 production and shorter survival time in patients with HCC. Critically, ZNT1 regulated endosomal Zn 2+ levels for endocytosis of toll-like receptor 4 and programmed cell death ligand 1, thereby decreasing macrophage-induced inflammation and immunosuppression to protect from liver tumors. Myeloid-specific deletion of ZNT1 in mice increased chronic inflammation, liver fibrosis, tumor numbers, and size. Notably, Zn supplementation could reduce inflammation and surface programmed cell death ligand 1 expression in macrophages with the increased CD8 + T cell cytotoxicity, which synergized the antitumor efficacy of Sorafenib/Lenvatinib.Our study proposes a new concept that ZNT1 and Zn regulate endosome endocytosis to maintain surface receptors, and Zn supplements might be synergized with chemotherapy to treat inflammation-associated tumors, especially those containing programmed cell death ligand 1 + myeloid cells.
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