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

当炎性疾病伴有免疫细胞或免疫调节组织（如肝脏）的大量细胞因子表达时，可能会导致致命的过程。这种全身性炎症反应（SIR）甚至可以在破坏性的“细胞因子风暴”中达到高潮，导致组织中许多过程的失调，从而导致广泛的损伤，特别是在肺部。因此，SIR的程度至关重要地决定了患者的生存。在德国，每天有250人死于sir伴随的败血症。同样，SIR也是胰腺炎和COVID-19死亡的一个主要原因。因此，通过有针对性的治疗干预来预防或减弱SIR对于降低炎症性疾病的严重程度是必要的。这需要对SIR开发的机制基础有更好的理解。我们之前和初步的研究表明，SIR发展的一个全新的分子机制涉及TIMP-1（金属蛋白酶组织抑制剂-1）的非规范细胞动力学信号活性。TIMP-1是一种多功能蛋白，其血浆水平与胰腺炎的严重程度相关。这种信号活动通过迄今未知的TIMP-1与不变量链（CD74）的相互作用发生，并引起免疫细胞的激活，免疫细胞代表了TIMP-1先前未识别的靶细胞实体。在这个项目中，我们旨在阐明TIMP-1在基因修饰（野生型和TIMP-1消融）小鼠全身炎症模型中对急性胰腺炎背景下SIR和SIR相关细胞因子风暴发展的影响。我们假设TIMP-1通过调节SIR相关组织中免疫细胞群的组成以及免疫细胞类型的表型（主要集中在巨噬细胞）导致急性胰腺炎SIR的发生。此外，分子途径分析将在体外进行免疫细胞和肝细胞，以及各自的共培养。在这里，我们通过表达cd74的肝细胞和免疫细胞检测细胞因子风暴是否由TIMP-1的非典型信号功能引起。最后，我们计划将我们的实验结果与患有炎症性疾病的患者样本的数据进行比较，以便将我们的发现转化为临床背景。预期的研究结果很可能不仅对已知的sir相关疾病有用，而且对新出现的疾病也有实际影响，例如COVID-19。在未来，干扰TIMP-1/CD74相互作用可能是一种有用的治疗策略。

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.