Objective Previous studies indicate that eosinophils are recruited into the allograft following orthotopic liver transplantation and protect from ischaemia reperfusion (IR) injury. In the current studies, we aim to explore whether their protective function could outlast during liver repair. Design Eosinophil-deficient mice and adoptive transfer of bone marrow-derived eosinophils (bmEos) were employed to investigate the effects of eosinophils on tissue repair and regeneration after hepatic IR injury. Aside from exogenous cytokine or neutralising antibody treatments, mechanistic studies made use of a panel of mouse models of eosinophil-specific IL-4/IL-13-deletion, cell-specific IL-4rα-deletion in liver macrophages and hepatocytes and macrophage-specific deletion of heparin-binding epidermal growth factor-like growth factor (hb-egf). Result We observed that eosinophils persisted over a week following hepatic IR injury. Their peak accumulation coincided with that of hepatocyte proliferation. Functional studies showed that eosinophil deficiency was associated with a dramatic delay in liver repair, which was normalised by the adoptive transfer of bmEos. Mechanistic studies demonstrated that eosinophil-derived IL-4, but not IL-13, was critically involved in the reparative function of these cells. The data further revealed a selective role of macrophage-dependent IL-4 signalling in liver regeneration. Eosinophil-derived IL-4 stimulated macrophages to produce HB-EGF. Moreover, macrophage-specific hb-egf deletion impaired hepatocyte regeneration after IR injury. Conclusion Together, these studies uncovered an indispensable role of eosinophils in liver repair after acute injury and identified a novel crosstalk between eosinophils and macrophages through the IL-4/HB-EGF axis. Data are available on reasonable request. All data relevant to the study are included in the article or uploaded as supplementary information.

中文翻译：

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嗜酸性粒细胞和巨噬细胞之间新型 IL-4/HB-EGF 依赖性串扰控制缺血和再灌注损伤后的肝脏再生

目的 先前的研究表明，原位肝移植后，嗜酸性粒细胞被募集到同种异体移植物中，并可防止缺血再灌注 (IR) 损伤。在当前的研究中，我们的目的是探讨它们的保护功能在肝脏修复过程中是否能够持续。设计采用嗜酸性粒细胞缺陷小鼠和骨髓源性嗜酸性粒细胞（bmEos）的过继转移来研究嗜酸性粒细胞对肝IR损伤后组织修复和再生的影响。除了外源性细胞因子或中和抗体治疗外，机制研究还利用了一组嗜酸性粒细胞特异性 IL-4/IL-13 缺失、肝巨噬细胞和肝细胞中细胞特异性 IL-4rα 缺失以及巨噬细胞特异性的小鼠模型。删除肝素结合表皮生长因子样生长因子（hb-egf）。结果 我们观察到肝 IR 损伤后嗜酸性粒细胞持续存在一周以上。它们的积累峰值与肝细胞增殖的峰值一致。功能研究表明，嗜酸性粒细胞缺乏与肝脏修复的显着延迟相关，而肝脏修复通过 bmEos 的过继转移而恢复正常。机制研究表明，嗜酸性粒细胞衍生的 IL-4（而非 IL-13）与这些细胞的修复功能密切相关。数据进一步揭示了巨噬细胞依赖性 IL-4 信号在肝再生中的选择性作用。嗜酸性粒细胞衍生的 IL-4 刺激巨噬细胞产生 HB-EGF。此外，巨噬细胞特异性 hb-egf 缺失会损害 IR 损伤后的肝细胞再生。结论 总之，这些研究揭示了嗜酸性粒细胞在急性损伤后肝脏修复中不可或缺的作用，并确定了嗜酸性粒细胞和巨噬细胞之间通过 IL-4/HB-EGF 轴的新型串扰。可根据合理要求提供数据。与研究相关的所有数据都包含在文章中或作为补充信息上传。