RIP2 Caspase-1 Signaling in Macrophages

巨噬细胞中的 RIP2 Caspase-1 信号转导

• 批准号: 8402150
• 负责人: Mark Damian Wewers
• 金额: $ 35.34万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-01-12 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8402150
• 关键词: AG 126; Affect; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Apoptosis; Biology; CASP1 gene; Caspase; Caspase-1; Cell Death; Cells; Cessation of life; Complex; Cytosol; Data; Disease; Down-Regulation; Enzyme Activation; Event; Homologous Gene; Host Defense; Immune response; Individual; Infection; Infectious Agent; Inflammation; Inflammatory; Inflammatory Response; Injury; Interleukin-18; Laboratories; Lead; Leucine; Link; Lung; Mediating; Membrane; Molecular; Outcome; Pathogenesis; Phosphorylation; Phosphotransferases; Plants; Play; Process; Protein Tyrosine Kinase; Proteins; RIPK2 gene; Regulation; Role; Sepsis; Septic Shock; Severities; Signal Transduction; System; Tyrphostins; United States; caspase-5; cytokine; improved; knockout animal; macrophage; marenostrin; mortality; novel therapeutic intervention; pathogen; protein complex; response; septic; trafficking

Project Summary Macrophage release of 17 kDa IL-1¿ is a highly regulated event that extends beyond the macrophage's ability to transcribe and synthesize the precursor, 31 kDa proIL-1¿. This event is centered upon activation of the enzyme caspase-1 and involves a complex protein assemblage termed the inflammasome. Inflammasome components are homologues of an ancient innate host defense system that exists in both plants and animals. The present proposal seeks to expand upon the clues derived from the macrophage biology of IL-1¿ and extend these processes to the basics of the host response to sepsis. We have recent data to demonstrate that key components of this intracellular inflammasome complex contribute significantly to the devastating activation of the innate host response that defines septic shock. More specifically, caspase-1, the central target of the inflammasome has been directly linked to sepsis. Not only are caspase-1 knockout animals protected from sepsis mortality but individual components of the caspase-1 inflammasome complex (e.g., caspase-5, ASC and NALP1) have also been linked to sepsis outcomes. These proteins interact with each other via caspase recruitment domains (CARDs) and structurally related pyrin domains (PYDs). Our hypothesis is that posttranslational events centered upon these CARD and PYD domains are central to the pathogenesis of sepsis. Inflammasome assembly not only regulates the processing and activation of inflammatory cytokines like IL-1¿ and IL-18 but extends to the regulation of NF¿B and host cell apoptosis. The current proposal seeks to apply these exciting breakthroughs in the biology of macrophage function to the challenge of sepsis. We know that one of the key regulatory events in inflammasome assembly is the triggering of CARD/CARD and PYD/PYD interactions. We have recently demonstrated that regulating CARD-containing molecules (e.g., RIP2 and ASC) can direct the caspase-1 centered inflammatory response either toward NF¿B or toward IL-1¿ processing. Interestingly, these events involve an early phosphorylation event since inhibition of tyrosine kinase activity profoundly affects the inflammasome and also protects animals from sepsis. Thus, this proposal seeks to dissect the molecular details of how these events are regulated. The central hypothesis is that the master regulatory switch that determines the direction and severity of the pro and anti-inflammatory responses to septic challenge are controlled in the cytosol by specific CARD/CARD and PYD/PYD interactions. We will dissect the mechanisms that regulate the ability of caspase-1 and RIP2 to interact, traffic to membranes and then direct host inflammation. These events initially induce NFkB activation but subsequently, via caspase-1 catalytic activation, may finally induce apoptosis and down regulation of NF¿B events. These studies will improve our understanding of the basic innate host responses to sepsis and in doing so uncover novel therapeutic approaches to septic shock and other inflammatory disorders that are regulated by this caspase-1-centric process.

项目概要 巨噬细胞释放 17 kDa IL-1¿是一个高度调控的事件，超出了巨噬细胞的范围 转录和合成前体 31 kDa proIL-1¿ 的能力此事件以 的激活为中心。 caspase-1 酶，涉及称为炎性小体的复杂蛋白质组装体。 这些成分是植物和动物中存在的古代先天宿主防御系统的同源物。 本提案旨在扩展源自 IL-1 巨噬细胞生物学的线索。和 将这些过程扩展到宿主对脓毒症反应的基础知识我们有最新的数据证明了这一点。 这种细胞内炎性体复合物的关键成分对毁灭性的破坏有重大贡献 激活先天性宿主反应，即败血性休克，更具体地说，是中枢 caspase-1。 炎症小体的靶标与脓毒症直接相关，不仅是 caspase-1 敲除动物。 可以防止败血症死亡，但 caspase-1 炎性体复合物的各个成分（例如， caspase-5、ASC 和 NALP1）也与脓毒症结果相关，这些蛋白质彼此相互作用。 其他通过半胱天冬酶招募结构域（CARD）和结构相关的吡啶结构域（PYD）。 假设以这些 CARD 和 PYD 结构域为中心的翻译后事件是 脓毒症的发病机制不仅调节炎症小体的加工和激活。 IL-1 等炎症细胞因子¿和 IL-18，但延伸至 NF 的调节B与宿主细胞凋亡有关。 当前的提案旨在将这些令人兴奋的突破应用于巨噬细胞生物学 我们知道炎症小体组装中的关键调节事件之一。 是 CARD/CARD 和 PYD/PYD 相互作用的触发，我们最近证明了这种调节。 含有 CARD 的分子（例如 RIP2 和 ASC）可以指导以 caspase-1 为中心的炎症反应 要么走向 NF¿ B 或针对 IL-1¿加工。 由于酪氨酸激酶活性的抑制深刻影响炎症小体并保护动物 因此，该提案旨在剖析这些事件如何调节的分子细节。 中心假设是，决定专业方向和严重程度的主监管开关 对脓毒症挑战的抗炎反应在细胞质中由特定的 CARD/CARD 控制， 我们将剖析调节 caspase-1 和 RIP2 能力的机制。 这些事件最初会诱导 NFkB 激活。 但随后，通过 caspase-1 催化激活，最终可能诱导细胞凋亡和 NF 下调乙 这些研究将提高我们对脓毒症和脓毒症的基本先天宿主反应的理解。 这样做揭示了感染性休克和其他炎症性疾病的新治疗方法 受这种以 caspase-1 为中心的过程的调节。

项目成果

MAIL regulates human monocyte IL-6 production.

MAIL 调节人单核细胞 IL-6 的产生。

• DOI: 10.4049/jimmunol.0802736
• 发表时间: 2009
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Seshadri,Sudarshan;Kannan,Yashaswini;Mitra,Srabani;Parker-Barnes,Jennifer;Wewers,MarkD
• 通讯作者: Wewers,MarkD