Lymphotoxin-β-receptor deficient (LTβR−/−) and Tumor Necrosis Factor Receptor p55 deficient (TNFRp55−/−) mice show defects in liver regeneration (LR) after partial hepatectomy (PHx) with significantly increased mortality. LTβR and TNFRp55 belong to the core members of the TNF/TNFR superfamily. Interestingly, combined failure of LTβR and TNFRp55 signaling after PHx leads to a complete defect in LR. Here, we first addressed the question which liver cell population crucially requires LTβR signaling for efficient LR. To this end, mice with a conditionally targeted LTβR allele (LTβRfl/fl) were crossed to AlbuminCre and LysozymeMCre mouse lines to unravel the function of the LTβR on hepatocytes and monocytes/macrophages/Kupffer cells, respectively. Analysis of these mouse lines clearly reveals that LTβR is required on hepatocytes for efficient LR while no deficit in LR was found in LTβRfl/fl × LysMCre mice. Second, the molecular basis for the cooperating role of LTβR and TNFRp55 signaling pathways in LR was investigated by transcriptome analysis of etanercept treated LTβR−/− (LTβR−/−/ET) mice. Bioinformatic analysis and subsequent verification by qRT-PCR identified novel target genes (Cyclin-L2, Fas-Binding factor 1, interferon-related developmental regulator 1, Leucyl-tRNA Synthetase 2, and galectin-4) that are upregulated by LTβR/TNFRp55 signaling after PHx and fail to be upregulated after PHx in LTβR−/−/ET mice.

中文翻译：

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部分肝切除术后肝再生需要肝细胞上的淋巴毒素-β-受体 (LTβR) 信号传导

淋巴毒素-β-受体缺陷（LTβR-/-) 和肿瘤坏死因子受体 p55 缺陷 (TNFRp55-/-) 小鼠在部分肝切除 (PHx) 后表现出肝再生 (LR) 缺陷，死亡率显着增加。LTβR 和 TNFRp55 属于 TNF/TNFR 超家族的核心成员。有趣的是，PHx 后 LTβR 和 TNFRp55 信号传导的联合失败导致 LR 完全缺陷。在这里，我们首先解决了哪个肝细胞群关键地需要 LTβR 信号传导来实现高效 LR 的问题。为此，具有条件靶向 LTβR 等位基因（LTβR佛罗里达州/佛罗里达州) 与白蛋白Cre 和溶菌酶MCre 小鼠系杂交，以分别揭示LTβR 对肝细胞和单核细胞/巨噬细胞/枯否细胞的功能。对这些小鼠品系的分析清楚地表明，肝细胞上需要 LTβR 以实现有效的 LR，而在 LTβR 中没有发现 LR 缺陷佛罗里达州/佛罗里达州× LysMCre 小鼠。其次，通过依那西普处理的 LTβR 的转录组分析，研究了 LTβR 和 TNFRp55 信号通路在 LR 中协同作用的分子基础。-/-(LTβR-/-/ET) 小鼠。通过 qRT-PCR 进行的生物信息学分析和随后的验证确定了由 LTβR/TNFRp55 信号传导上调的新靶基因（细胞周期蛋白-L2、Fas 结合因子 1、干扰素相关发育调节因子 1、亮氨酰-tRNA 合成酶 2 和半乳糖凝集素-4） PHx 后，在 LTβR 中 PHx 后未能上调-/-/ET 小鼠。