Objective Kupffer cells (KCs) protect against hepatocellular carcinoma (HCC) by communicating with other immune cells. However, the underlying mechanism(s) of this process is incompletely understood. Design FVB/NJ mice were hydrodynamically injected with AKT/Ras and Sleeping Beauty transposon to induce HCC. Mini-circle and Sleeping Beauty were used to overexpress microRNA-206 in KCs of mice. Flow cytometry and immunostaining were used to evaluate the change in the immune system. Results Hydrodynamic injection of AKT/Ras into mice drove M2 polarisation of KCs and depletion of cytotoxic T cells (CTLs) and promoted HCC development. M1-to-M2 transition of KCs impaired microRNA-206 biogenesis. By targeting Klf4 (kruppel like factor 4) and, thereby, enhancing the production of M1 markers including C-C motif chemokine ligand 2 (CCL2), microRNA-206 promoted M1 polarisation of macrophages. Indeed, microRNA-206-mediated increase of CCL2 facilitated hepatic recruitment of CTLs via CCR2. Disrupting each component of the KLF4/CCL2/CCR2 axis impaired the ability of microRNA-206 to drive M1 polarisation of macrophages and recruit CTLs. In AKT/Ras mice, KC-specific expression of microRNA-206 drove M1 polarisation of KCs and hepatic recruitment of CTLs and fully prevented HCC, while 100% of control mice died from HCC. Disrupting the interaction between microRNA-206 and Klf4 in KCs and depletion of CD8+ T cells impaired the ability of miR-206 to prevent HCC. Conclusions M2 polarisation of KCs is a major contributor of HCC in AKT/Ras mice. MicroRNA-206, by driving M1 polarisation of KCs, promoted the recruitment of CD8+ T cells and prevented HCC, suggesting its potential use as an immunotherapeutic approach. All data relevant to the study are included in the article or uploaded as supplementary information.

中文翻译：

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MicroRNA-206 通过驱动 Kupffer 细胞的 M1 极化促进 CD8+ T 细胞的募集

目的枯否细胞（KCs）通过与其他免疫细胞通讯来预防肝细胞癌（HCC）。然而，这一过程的基本机制尚不完全清楚。设计的 FVB/NJ 小鼠被流体动力学地注射 AKT/Ras 和睡美人转座子以诱导 HCC。Mini-circle 和 Sleeping Beauty 用于在小鼠的 KCs 中过表达 microRNA-206。流式细胞术和免疫染色用于评估免疫系统的变化。结果 AKT/Ras 的水动力注射到小鼠体内驱动了 KCs 的 M2 极化和细胞毒性 T 细胞 (CTLs) 的消耗，并促进了 HCC 的发展。KCs 的 M1 到 M2 转换损害了 microRNA-206 的生物发生。通过靶向 Klf4（kruppel 样因子 4），从而增强包括 CC 基序趋化因子配体 2 (CCL2) 在内的 M1 标志物的产生，microRNA-206 促进巨噬细胞的 M1 极化。事实上，microRNA-206 介导的 CCL2 增加通过 CCR2 促进了 CTL 的肝脏募集。破坏 KLF4/CCL2/CCR2 轴的每个成分会损害 microRNA-206 驱动巨噬细胞 M1 极化和募集 CTL 的能力。在 AKT/Ras 小鼠中，microRNA-206 的 KC 特异性表达驱动了 KCs 的 M1 极化和 CTLs 的肝脏募集，并完全预防了 HCC，而 100% 的对照小鼠死于 HCC。破坏 KCs 中 microRNA-206 和 Klf4 之间的相互作用以及 CD8+ T 细胞的消耗会损害 miR-206 预防 HCC 的能力。结论 KCs 的 M2 极化是 AKT/Ras 小鼠 HCC 的主要贡献者。MicroRNA-206 通过驱动 KCs 的 M1 极化，促进 CD8+ T 细胞的募集并预防 HCC，表明其作为免疫治疗方法的潜在用途。所有与研究相关的数据都包含在文章中或作为补充信息上传。