TIMP-1-Signaling as New Trigger of Systemic Inflammatory Response (SIR)

点击翻译按钮获取中文摘要

Inflammatory diseases may take a fatal course when they are accompanied by massive cytokine expression by immune cells or immune-modulatory tissues such as the liver. Such Systemic Inflammatory Response (SIR) even can culminate in a devastating ‘cytokine storm’, which leads to de-regulation of so many processes in tissues resulting in extensive damage, especially in the lungs. Therefore, the extent of SIR critically determines patient survival. In Germany, 250 people die of SIR-accompanied sepsis every day. Likewise, SIR represents one major cause of death in pancreatitis as well as in COVID-19. Therefore, prevention or attenuation of SIR by targeted therapeutic interference is necessary to reduce severity of inflammatory diseases. This requires a better understanding of the mechanistic basis of SIR development. Our previous and preliminary work towards this project suggests a completely new molecular mechanism of SIR development, which involves the non-canonical cytokinic signaling activity of TIMP-1 (tissue inhibitor of metalloproteinases-1). TIMP-1 is a multi-functional protein, whose plasma levels correlate with severity of pancreatitis. This signaling activity occurs via a so far unknown interaction of TIMP-1 with invariant chain (CD74) and causes activation of immune cells, which represent a previously unidentified target cell entity for TIMP-1. In this project, we aim to elucidate the impact of TIMP-1 on development of SIR and SIR-associated cytokine storm in the context of acute pancreatitis in genetically modified (wildtype and TIMP-1-ablated) mouse models of systemic inflammation. We hypothesize that TIMP-1 causes the development of SIR in acute pancreatitis by modulating the composition of immune cell populations in SIR-relevant tissues as well as the phenotype of immune cell types, primarily focusing on macrophages. In addition, molecular pathway analyses will be performed in vitro with immune cells and hepatocytes, and respective co-cultures. Here, we test whether the cytokine storm is caused by the non-canonical signaling function of TIMP-1 via CD74-expressing hepatocytes and immune cells. Finally, we plan to compare our experimental results with data from samples of patients suffering from inflammatory diseases in order to translate our findings into the clinical context. The expected findings will very likely not only be useful and actual impact on known SIR-associated diseases, but also emerging ones, such as COVID-19. In the future, interference with TIMP-1/CD74 interaction may be one useful therapeutic strategy.