Inflammatory Caspases in Innate Immunity and Inflammation

描述（由申请人提供）：先天免疫系统包括几类模式识别受体，包括Toll样受体（TLR）和NOD样受体（NLR）。一组NLR家族成员形成称为“炎性小体”的多蛋白复合物，其含有衔接蛋白ASC和半胱天冬酶-1，并促进半胱天冬酶-1活化和IL-1和IL-18的成熟，其分泌导致强有力的炎症反应。Caspase-1是炎性Caspase的原型成员，是多种炎性、感染性和自身免疫性疾病的关键靶点。研究表明，caspase-1缺陷小鼠对脂多糖、大肠杆菌、 大肠杆菌诱导的休克和细胞凋亡。有趣的是，IL-1和IL-18，这两种主要的caspase-1下游靶分子不参与，表明caspase-1的一些其他下游靶是重要的。此外，我们的研究表明，常用的caspase-1缺陷小鼠系也缺乏caspase-11，这表明归因于caspase-1的炎症功能可能是caspase-1和caspase-11的联合作用。该提案将解决中心假设，即NLR/caspase-1和caspase-11信号轴在对微生物病原体的先天免疫中起着至关重要的作用。我们在蛋白质组范围的筛选中确定了几种重要的caspase-1底物，我们的初步数据表明这些底物在炎症和脓毒症诱导中起关键作用。总之，这项研究将阐明caspase-1和caspase-11及其效应机制在先天免疫和炎症中的作用，并将有助于确定调节先天免疫和炎症的分子和细胞机制，从而为炎症和感染性疾病提供新的治疗靶点。 公共卫生相关性：先天免疫系统对微生物感染的识别导致急性炎症反应，有助于消除入侵的病原体。本研究的重点是了解关键细胞蛋白在复杂的分子和细胞炎症机制中的作用。拟议研究的结果将揭示NLR/caspase-1级联功能的新元素和炎症中的信号通路，从而有助于发现治疗炎症相关疾病的有效疗法。

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. PUBLIC HEALTH RELEVANCE: Recognition of microbial infection by the innate immune system results in acute inflammatory responses that help to eliminate the invading pathogens. This research focuses on understanding the role of key cellular proteins in the complex molecular and cellular inflammatory mechanisms. The outcomes of the proposed studies will reveal new elements of NLR/caspase-1 cascade function and the signaling pathways in inflammation and thus will help in the discovery of effective therapeutics to treat inflammation associated diseases.