Kupffer cells (KCs), which are liver-resident macrophages, originate from the fetal yolk sac and represent one of the largest macrophage populations in the body. However, the current data on the origin of the cells that restore macrophages during liver injury and regeneration remain controversial. Here, we address the question of whether liver macrophage restoration results from circulating monocyte infiltration or local KC proliferation in regenerating livers after partial hepatectomy (PHx) and uncover the underlying mechanisms. By using several strains of genetically modified mice and performing immunohistochemical analyses, we demonstrated that local KC proliferation mainly contributed to the restoration of liver macrophages after PHx. Peak KC proliferation was impaired in Il6-knockout (KO) mice and restored after the administration of IL-6 protein, whereas KC proliferation was not affected in Il4-KO or Csf2-KO mice. The source of IL-6 was identified using hepatocyte- and myeloid-specific Il6-KO mice and the results revealed that both hepatocytes and myeloid cells contribute to IL-6 production after PHx. Moreover, peak KC proliferation was also impaired in myeloid-specific Il6 receptor-KO mice after PHx, suggesting that IL-6 signaling directly promotes KC proliferation. Studies using several inhibitors to block the IL-6 signaling pathway revealed that sirtuin 1 (SIRT1) contributed to IL-6-mediated KC proliferation in vitro. Genetic deletion of the Sirt1 gene in myeloid cells, including KCs, impaired KC proliferation after PHx. In conclusion, our data suggest that KC repopulation after PHx is mainly driven by local KC proliferation, which is dependent on IL-6 and SIRT1 activation in KCs.

枯否细胞 (KCs) 是肝脏中的巨噬细胞，起源于胎儿卵黄囊，是体内最大的巨噬细胞群之一。然而，目前关于在肝损伤和再生过程中恢复巨噬细胞的细胞来源的数据仍然存在争议。在这里，我们解决了肝巨噬细胞恢复是否是由于部分肝切除术（PHx）后再生肝脏中循环单核细胞浸润或局部 KC 增殖的结果，并揭示了潜在的机制。通过使用几种转基因小鼠品系并进行免疫组织化学分析，我们证明局部 KC 增殖主要有助于 PHx 后肝巨噬细胞的恢复。Il6中的峰值 KC 增殖受损敲除 (KO) 小鼠并在给予 IL-6 蛋白后恢复，而在 Il4 -KO 或 Csf2 -KO 小鼠中不影响KC增殖。使用肝细胞和骨髓特异性Il6 - KO 小鼠鉴定 IL-6 的来源，结果显示肝细胞和骨髓细胞都有助于 PHx 后 IL-6 的产生。此外，PHx 后骨髓特异性Il6受体-KO 小鼠的峰值 KC 增殖也受损，这表明 IL-6 信号传导直接促进 KC 增殖。使用几种抑制剂阻断 IL-6 信号通路的研究表明，sirtuin 1 (SIRT1) 在体外有助于 IL-6 介导的 KC 增殖。Sirt1的基因缺失骨髓细胞中的基因，包括 KCs，在 PHx 后损害 KC 增殖。总之，我们的数据表明，PHx 后的 KC 再增殖主要由局部 KC 增殖驱动，这取决于 KCs 中的 IL-6 和 SIRT1 激活。