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

当炎症性疾病伴随免疫细胞或免疫调节组织（如肝脏）大量表达细胞因子时，它们可能会发生致命的过程。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，这导致组织中如此多的过程失调，从而导致广泛的损伤，特别是在肺部。因此，SIR的程度决定了患者的生存率。在德国，每天有250人死于SIR伴随的败血症。同样，SIR是胰腺炎和COVID-19死亡的主要原因之一。因此，通过靶向治疗干预预防或减弱SIR对于降低炎性疾病的严重程度是必要的。这需要更好地理解SIR发展的机制基础。我们以前的和初步的工作对这个项目提出了一个全新的分子机制SIR的发展，这涉及到非经典的TIMP-1（组织抑制剂金属蛋白酶-1）的细胞因子信号活性。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。这种信号传导活性通过TIMP-1与不变链（CD 74）的迄今未知的相互作用发生，并引起免疫细胞的活化，其代表TIMP-1的先前未鉴定的靶细胞实体。在这个项目中，我们的目的是阐明TIMP-1的发展的SIR和SIR相关的细胞因子风暴在急性胰腺炎的背景下，在遗传修饰（野生型和TIMP-1消融）小鼠模型的全身炎症的影响。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），导致急性胰腺炎中SIR的发展。此外，将在体外对免疫细胞和肝细胞以及各自的共培养物进行分子途径分析。在这里，我们测试细胞因子风暴是否由TIMP-1通过表达CD 74的肝细胞和免疫细胞的非经典信号传导功能引起。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。预期的发现很可能不仅对已知的SIR相关疾病有用和实际影响，而且对新出现的疾病，如COVID-19也有影响。在未来，干扰TIMP-1/CD 74相互作用可能是一个有用的治疗策略。

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.