Apolipoprotein A4 regulates the immune response in carbon tetrachloride-induced chronic liver injury in mice
Apolipoprotein A4 regulates the immune response in carbon tetrachloride-induced chronic liver injury in mice
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载脂蛋白A4调节四氯化碳诱导的小鼠慢性肝损伤的免疫反应
DOI：
10.1016/j.intimp.2020.107222
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发表时间：
2021-01-01
影响因子：
5.6
通讯作者：
Li, Shengbin
中科院分区：
文献类型：
--
作者：
Wang, Yinan;Yang, Ziyu;Li, Shengbin
本文探讨了载脂蛋白A4在四氯化碳诱导的慢性肝损伤（CLI）小鼠模型中的作用。将C57 BL/6 J小鼠（WT）和ApoA 4敲除（KO）小鼠分为CCl 4 CLI（WT-CCl 4和KO-CCl 4）和橄榄油溶剂对照组（WT-Veh和KO-Veh）。一些KO-CCl 4小鼠另外用重组小鼠ApoA 4和原代小鼠T淋巴细胞注射处理。6周后，进行组织学分析、生化和超氧化物歧化酶（SOD）和丙二醛（MDA）测定、免疫细胞的流式细胞术和qRT-PCR分析。与WT-CCl 4相比，CCl 4治疗后KO小鼠显示肝脏SOD活性降低，血清MDA活性升高，导致肝损伤和纤维化恶化，同时伴有肝脏α平滑肌肌动蛋白增强（α-SMA）、金属蛋白酶组织抑制剂-1（TIMP-1）和I型胶原α 1链（COL 1A 1）转运蛋白、巨噬细胞M1水平升高、肿瘤坏死因子-α增强（TNF-α）、白细胞介素6（IL-6）和C-C基序趋化因子配体5（CCL 5）的转录，但降低白细胞介素10（IL-10）、单核细胞趋化蛋白1（MCP-1）、C-C基序趋化因子受体2（CCR 2）、C-X3-C基序趋化因子受体1（CX 3CR 1）和C-X-C基序趋化因子配体9（CXCL 9）的转录，以及降低CD 3+，肝组织、血细胞和脾脏中的CD 4+和CD 8 + T细胞百分比。此外，CD 11b + CD 115+、CD 11b +/Ly 6C（high）、CD 11b +/LyC 6和CD 11b +/Ly 6C（int）细胞增加，ApoA 4蛋白和T细胞注射可部分逆转这种情况。结论：ApoA 4可能通过抑制肝纤维化介质和炎性细胞因子、抑制促炎性肝M1细胞侵袭以及调节CD 8 + T和CD 4 + T淋巴细胞参与肝脏保护作用。
This article explores the role of ApoA4 in a CCl4-induced chronic liver injury (CLI) mouse model. C57BL/6J mice (WT) and ApoA4 knock-out (KO) mice were divided into CCl4 CLI (WT-CCl4 and KO-CCl4) and olive oil solvent control groups (WT-Veh and KO-Veh). Some of the KO-CCl4 mice were additionally treated with recombinant mouse ApoA4 and primary mouse T lymphocyte injections. After 6 weeks, histological analyses, biochemical and superoxide dismutase (SOD) and malondialdehyde (MDA) assays, flow cytometry of immune cells and qRT-PCR analyses were performed. KO mice after treatment with CCl4 showed reduced hepatic SOD and enhanced serum MDA activities leading to worsening liver injury and fibrosis compared with WT-CCl4, accompanied by enhanced hepatic alpha smooth muscle actin (alpha-SMA), tissue inhibitor of metalloproteinases-1 (TIMP-1) and collagen type I alpha 1 chain (COL1A1) transcriptions, elevated macrophage M1 levels, enhanced tumor necrosis factor-alpha (TNF-alpha), Interleukin 6 (IL-6) and C-C Motif Chemokine Ligand 5 (CCL5), but reduced Interleukin 10 (IL-10), monocyte chemotactic protein 1 (MCP-1), C-C Motif Chemokine Receptor 2 (CCR2), C-X3-C Motif Chemokine Receptor 1 (CX3CR1) and C-X-C Motif Chemokine Ligand 9 (CXCL9) transcription, as well as reduced CD3+, CD4+ and CD8+ T cell percentages in hepatic tissue, blood cells and spleen. In addition, CD11b+CD115+, CD11b+/Ly6C(high), CD11b+/LyC6 and CD11b+/Ly6C(int) cells were enhanced, which partly reversed by ApoA4 protein and T cell injections. In conclusion, we propose that ApoA4 might be involved in liver protection via inhibiting fibrotic mediators and inflammatory cytokines, suppression of pro-inflammatory hepatic M1 cell invasion and regulation of CD8+ T and CD4+ T lymphocytes.