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LIFR regulates cholesterol-driven bidirectional hepatocyte–neutrophil cross-talk to promote liver regeneration
Nature Metabolism ( IF 18.9 ) Pub Date : 2024-08-15 , DOI: 10.1038/s42255-024-01110-y
Yalan Deng 1 , Zilong Zhao 2 , Marisela Sheldon 1 , Yang Zhao 1 , Hongqi Teng 1 , Consuelo Martinez 1 , Jie Zhang 1 , Chunru Lin 2 , Yutong Sun 2 , Fan Yao 1, 3 , Michael A Curran 4, 5 , Hao Zhu 6 , Li Ma 1, 5
Affiliation  

Liver regeneration is under metabolic and immune regulation. Despite increasing recognition of the involvement of neutrophils in regeneration, it is unclear how the liver signals to the bone marrow to release neutrophils after injury and how reparative neutrophils signal to hepatocytes to reenter the cell cycle. Here we report that loss of the liver tumour suppressor Lifr in mouse hepatocytes impairs, whereas overexpression of leukaemia inhibitory factor receptor (LIFR) promotes liver repair and regeneration after partial hepatectomy or toxic injury. In response to physical or chemical damage to the liver, LIFR from hepatocytes promotes the secretion of cholesterol and CXCL1 in a STAT3-dependent manner, leading to the efflux of bone marrow neutrophils to the circulation and damaged liver. Cholesterol, via its receptor ERRα, stimulates neutrophils to secrete hepatocyte growth factor to accelerate hepatocyte proliferation. Altogether, our findings reveal a LIFR–STAT3–CXCL1–CXCR2 axis and a LIFR–STAT3–cholesterol–ERRα–hepatocyte growth factor axis that form bidirectional hepatocyte–neutrophil cross-talk to repair and regenerate the liver.



中文翻译:


LIFR 调节胆固醇驱动的双向肝细胞-中性粒细胞串扰以促进肝脏再生



肝脏再生受到代谢和免疫调节。尽管人们越来越认识到中性粒细胞参与再生,但尚不清楚肝脏如何在受伤后向骨髓发出信号以释放中性粒细胞,以及修复性中性粒细胞如何向肝细胞发出信号以重新进入细胞周期。在这里,我们报道了小鼠肝细胞中肝肿瘤抑制因子 Lifr 的缺失受损,而白血病抑制因子受体 (LIFR) 的过表达促进了部分肝切除术或中毒性损伤后的肝脏修复和再生。为了响应对肝脏的物理或化学损伤,来自肝细胞的 LIFR 以 STAT3 依赖性方式促进胆固醇和 CXCL1 的分泌,导致骨髓中性粒细胞外流到循环和肝脏受损。胆固醇通过其受体 ERRα 刺激中性粒细胞分泌肝细胞生长因子以加速肝细胞增殖。总而言之,我们的研究结果揭示了一个 LIFR-STAT3-CXCL1-CXCR2 轴和一个 LIFR-STAT3-胆固醇-ERRα-肝细胞生长因子轴,它们形成双向肝细胞-中性粒细胞串扰以修复和再生肝脏。

更新日期:2024-08-15
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