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.

库普弗细胞 (KC) 是肝脏驻留的巨噬细胞，起源于胎儿卵黄囊，是体内最大的巨噬细胞群之一。然而，目前关于肝损伤和再生过程中恢复巨噬细胞的细胞起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部分肝切除（PHx）后再生肝脏中循环单核细胞浸润或局部 KC 增殖引起的问题，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 后肝脏巨噬细胞的恢复。在IL6敲除(KO)小鼠中KC增殖峰值受到损害，并且在施用IL-6蛋白后恢复，而在Il4 -KO或Csf2 -KO小鼠中KC增殖不受影响。使用肝细胞和骨髓特异性Il6- KO小鼠鉴定了IL-6的来源，结果显示肝细胞和骨髓细胞在PHx后均有助于IL-6的产生。此外，在 PHx 后，骨髓特异性IL6受体 KO 小鼠的 KC 增殖峰值也受到损害，表明 IL-6 信号传导直接促进 KC 增殖。使用多种抑制剂阻断 IL-6 信号通路的研究表明，sirtuin 1 (SIRT1) 有助于 IL-6 介导的体外 KC 增殖。包括 KC 在内的骨髓细胞中Sirt1基因的遗传缺失会损害 PHx 后 KC 的增殖。总之，我们的数据表明 PHx 后 KC 重新增殖主要由局部 KC 增殖驱动，这依赖于 KC 中 IL-6 和 SIRT1 的激活。