Kupffer cell restoration after partial hepatectomy is mainly driven by local cell proliferation in IL-6-dependent autocrine and paracrine manners
Kupffer cell restoration after partial hepatectomy is mainly driven by local cell proliferation in IL-6-dependent autocrine and paracrine manners
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DOI：
10.1038/s41423-021-00731-7
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发表时间：
2021-07-19
影响因子：
24.1
通讯作者：
Gao, Bin
中科院分区：
文献类型：
--
作者：
Ahmed, Yeni Ait;Fu, Yaojie;Gao, Bin
枯否细胞（KCs）是肝脏中的巨噬细胞，起源于胚胎卵黄囊，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期间恢复巨噬细胞的细胞来源的数据仍然存在争议。在这里，我们解决的问题，是否肝巨噬细胞的恢复结果循环单核细胞浸润或局部KC增殖再生肝部分肝切除术（PHx）后，并揭示了潜在的机制。通过使用几种转基因小鼠和进行免疫组化分析，我们证明了局部KC增殖主要有助于PHx后肝巨噬细胞的恢复。在IL-6基因敲除（KO）小鼠中KC增殖峰值受损，并且在施用IL-6蛋白后恢复，而在IL-4基因敲除或Csf 2基因敲除小鼠中KC增殖不受影响。使用肝细胞和骨髓特异性IL-6-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，峰值KC增殖也在PHx后骨髓特异性IL-6受体KO小鼠中受损，表明IL-6信号直接促进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（SIRT 1）有助于IL-6介导的KC体外增殖。髓系细胞（包括KC）中Sirt 1基因的遗传缺失损害PHx后KC的增殖。总之，我们的数据表明PHx后KC再增殖主要由局部KC增殖驱动，这依赖于KC中的IL-6和SIRT 1激活。
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.