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

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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.