Mechanisms controlling pro-inflammatory mast cell functions and implications for chronic liver disease and cancer

肥大细胞(Mast cell，MC)是髓系造血细胞，参与先天免疫和获得性免疫过程。MCs因其在过敏和过敏反应中的有害作用而广为人知，但也参与伤口愈合、血管生成和调节肿瘤生长的过程。目前的研究表明，MCs在肝脏疾病(如肝纤维化和肝细胞癌)的发生和发展中的作用尚不清楚。肝细胞癌是一种由慢性肝脏炎症、纤维化和肝硬变引起的原发性肝癌。这一致病序列是由可溶性介质驱动的，如转化生长因子-β，这是不同的常驻细胞(肝细胞、肝星状细胞)和浸润性细胞(如MC)复杂的串扰所产生的结果。此外，我们最近已经证明，肝癌的发生本质上需要细胞周期调节因子Cyclin E1。我们的初步数据表明，细胞周期机制和转化生长因子-β1信号通路对MC生物学以及肝脏的MC功能都有重要贡献。例如，我们发现Cyclin E1也参与MC分化和MC依赖的促炎细胞因子的产生，如IL-6。此外，我们还发现转化生长因子-β-1共受体endoglin改变了MC的分化及其S效应的功能。最后，我们的初步数据表明，有癌前损伤的小鼠肝脏中有MC的积累，如晚期纤维化和肿瘤病变。综上所述，我们目前的知识表明，Cyclin E1和转化生长因子β相关信号是正常肥大细胞功能和肝癌发生所必需的。因此，本研究的首要目标是在慢性肝病的背景下，对MC的细胞周期和转化生长因子-β相关机制进行全面的分析。在肥大细胞生物学(HUBER)、细胞周期调控(LIEDTKE)、转化生长因子-β信号转导(WEEDKIRCHEN/MEURR)和肝病动物模型(LIEDTKE/WEISKIRCHEN/MEURR)方面，一组专家将讨论这一适时课题。为此，我们建议彻底评估细胞周期介体和转化生长因子-β相关信号分子在MC发育、分化和激活过程中的作用。此外，我们将建立新的小鼠模型，允许跟踪、耗尽和调节MCs，最后我们将确定E-型细胞周期蛋白和ENG在MCs中在慢性肝病和肝癌发展中的作用。这项计划将极大地扩展我们对肥大细胞生物学和肥大细胞在疾病肝脏中的功能的认识，从而为肝癌的治疗寻找新的靶点。

Mast cells (MCs) are hematopoietic cells of the myeloid lineage, which can take part in processes of innate and adaptive immunity. MCs are best known for their detrimental role in allergy and anaphylaxis, but are also involved in processes of wound healing, angiogenesis, and modulation of tumor growth.Current research has suggested a yet poorly understood function of MCs for initiation and progression of liver disease such as liver fibrosis and hepatocellular carcinoma (HCC). HCC is a primary liver cancer arising as a consequence of chronic liver inflammation, fibrosis and cirrhosis. This pathogenic sequence is driven by soluble mediators such as TGF-β released as a result of an intricate crosstalk by different resident (hepatocytes, hepatic stellate cells) and infiltrating cells (such as MCs). In addition, we have recently demonstrated that the initiation of liver cancer essentially requires the cell cycle mediator Cyclin E1.Our preliminary data points to important contributions of the cell cycle machinery and TGF-β1 signaling pathways for MC biology in general, but also for MC functions in the liver. For instance, we found that Cyclin E1 is also involved in MC differentiation and MC-dependent production of pro-inflammatory cytokines such as interleukin-6. In addition, we found that MC differentiation and it´s effector function is modified by the TGF-β1 co-receptor Endoglin (ENG). Finally, our preliminary data indicated the accumulation of MCs in murine livers with pre-cancerous injury such as advanced fibrosis and tumorous lesions. Altogether, our current knowledge suggests that Cyclin E1- and TGF-β-related signals are required for proper mast cell function and for hepatocarcinogenesis. Yet the underlying mechanisms are poorly understood.The overarching goal of this proposal is therefore a comprehensive analysis of cell cycle and TGF-β related mechanisms in MCs in the context of chronic hepatic diseases. This timely topic will be addressed by a group of experts with outstanding synergistic expertise of the applicants in mast cell biology (Huber), cell cycle regulation (Liedtke), TGF-β signaling (Weiskirchen/Meurer) and animal models of liver disease (Liedtke/Weiskirchen/Meurer).To this end, we propose to thoroughly evaluate the contributions of cell cycle mediators and TGF-β-related signaling molecules during development, differentiation and activation of MCs. Moreover, we will establish novel mouse models, allowing tracking, depleting and modulating MCs, and finally we will identify the contributions of E-type cyclins and ENG in MCs during chronic liver disease and liver cancer development.This project will largely expand our knowledge on mast cell biology and mast cell functions in the diseased liver with the option to identify new targets for the treatment of liver cancer.