Inflammatory Caspases in Innate Immunity and Inflammation

描述(申请人提供)：先天免疫系统包括几类模式识别受体，包括Toll样受体(TLRs)和Nod样受体(NLRs)。一组NLR家族成员形成一个被称为炎症体的多蛋白复合体，该复合体包含适配蛋白ASC和caspase-1，并促进caspase-1的激活和IL-1β和IL-18的成熟，分泌的IL-1和IL-18导致强大的炎症反应。Caspase-1是炎症性caspase的典型成员，是多种炎症性、感染性和自身免疫性疾病的关键靶点。研究表明，caspase-1缺陷小鼠对内毒素大肠杆菌的毒性作用具有抵抗力。 大肠埃希氏菌引起的休克和细胞凋亡。有趣的是，caspase-1的两个主要下游靶分子IL-1和IL-18没有参与，这表明caspase-1的其他下游靶分子是重要的。此外，我们的研究表明，常用的caspase-1缺陷小鼠系也缺乏caspase-11，这表明caspase-1的炎症功能可能是caspase-1和caspase-11共同作用的结果。这一建议将解决核心假设，即NLR/caspase-1和caspase-11信号轴在对微生物病原体的先天免疫中发挥关键作用。我们在蛋白质组筛选中确定了几个重要的caspase-1底物，初步数据表明，这些底物在炎症和败血症诱导中发挥了关键作用。总之，本研究将阐明caspase-1和caspase-11在先天免疫和炎症中的作用及其效应机制，并将有助于识别调节先天免疫和炎症的分子和细胞机制，从而为炎症性和感染性疾病提供新的治疗靶点。

DESCRIPTION (provided by applicant): The innate immune system comprises several classes of pattern recognition receptors, including Toll- like receptors (TLRs) and NOD-like receptors (NLRs). A set of NLR family members form a multi-protein complex termed 'the inflammasome', which contains the adaptor protein ASC and caspase-1, and promotes caspase-1 activation and maturation of IL-1¿ and IL-18, the secretion of which leads to a potent inflammatory response. Caspase-1 is the prototypical member of the inflammatory caspases and is a key target in several inflammatory, infectious and autoimmune diseases. Studies show that caspase-1-deficient mice are resistant to the toxic effects of lipopolysaccharide, Escherichia coli-induced shock, and apoptotic cell death. Interestingly, IL-1¿ and IL-18, the two major downstream target molecules of caspase-1 are not involved suggesting that some other downstream targets of caspase-1 are important. Additionally, our studies show that the commonly used lines of caspase-1-deficient mice are also deficient in caspase-11 suggesting that the inflammatory functions attributed to caspase-1 could be the combined actions of both caspase-1 and caspase-11. This proposal will address the central hypothesis that NLR/caspase-1 and caspase-11 signaling axis plays a crucial role in innate immunity to microbial pathogens. We identified several important caspase-1 substrates in a proteome-wide screen and our preliminary data suggest a key role for a set of these substrates in inflammation and sepsis induction. Overall, this study will elucidate the roles of caspase-1 and caspase-11 and their effector mechanisms in innate immunity and inflammation and will help identify the molecular and cellular mechanisms regulating innate immunity and inflammation, thus leading to novel therapeutic targets for inflammatory and infectious diseases.