Role of Eosinophils in Hepatic Ischemia Reperfusion Injury

项目总结 本建议的目的是研究嗜酸性粒细胞在肝脏缺血和缺氧时的功能作用。 再灌注损伤(IRI)。肝脏IRI是主要肝脏疾病发病率和死亡率的重要来源 手术切除和肝移植期间。先前的研究表明，肝移植后 天然免疫细胞，如中性粒细胞或巨噬细胞，被激活并进入同种异体肝移植。 出乎意料的是，我们观察到在原位肝移植后，嗜酸性粒细胞也在肝脏中聚集。 在人类身上进行移植。相比之下，我们在健康的肝活检中没有检测到任何嗜酸性粒细胞。同样， 在小鼠模型中，在肝脏IRI后，嗜酸性粒细胞在肝脏中以时间依赖的方式积聚。 利用遗传和抗体去除嗜酸性粒细胞的功能研究表明， 这些细胞在肝脏IRI期间。嗜酸性粒细胞耗竭后基因表达谱的无偏筛选 与嗜酸性粒细胞依赖的ST2参与肝脏保护有关。遗传和领养转移研究相结合 提示嗜酸性粒细胞特异性IL-33/ST2信号通路通过以下途径减轻缺血肝脏的炎症反应 抑制肝中性粒细胞聚集/激活。这些发现导致了我们的假设 肝脏IRI，嗜酸性粒细胞通过IL-33/ST2信号途径保护肝脏。提出了三个具体目标 为了研究嗜酸性粒细胞和IL-33/ST2信号在肝脏IRI中的作用，II)通过 嗜酸性粒细胞中的IL-33/ST2信号对肝脏IRI的保护作用，以及III)靶向IL-33/ST2信号在 嗜酸性粒细胞治疗肝脏IRI。

PROJECT SUMMARY The goal of this proposal is to investigate the functional role of eosinophils during hepatic ischemia and reperfusion injury (IRI). Hepatic IRI is a significant source of morbidity and mortality during major hepatic resection and during liver transplantation. Previous studies have shown that following liver transplantation innate immune cells, such as neutrophils or macrophages, are activated and traffic into the hepatic allograft. Unexpectedly, we observed that eosinophils also accumulate in the liver following orthotopic liver transplantation in humans. In contrast, we could not detect any eosinophils in healthy liver biopsies. Similarly, in a murine model, eosinophils accumulate in the liver in a time-dependent fashion following hepatic IRI. Functional studies using genetic and antibody-based depletion of eosinophils demonstrate a protective role of these cells during hepatic IRI. An unbiased screen of gene expression profiles following eosinophil depletion implicated eosinophil-dependent ST2 in liver protection. Combination of genetic and adoptive transfer studies suggest that eosinophil-specific IL-33/ST2 signaling attenuates inflammation of the ischemic liver by dampening hepatic neutrophil accumulation/activation. These findings led to our hypothesis that during hepatic IRI, eosinophils protect the liver through IL-33/ST2 signaling. Three Specific Aims are proposed to i) investigate the role of eosinophils and IL-33/ST2 signaling in hepatic IRI, ii) elucidate the mechanism by which IL-33/ST2 signaling in eosinophils protects against hepatic IRI, and iii) Target IL-33/ST2 signaling in eosinophils for the treatment of hepatic IRI.