Host-derived extracellular vesicles in inflammatory caspase activation

宿主来源的细胞外囊泡在炎症半胱天冬酶激活中的作用

• 批准号: 9973550
• 负责人: Vijay Rathinam
• 金额: $ 41万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-16 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9973550
• 关键词: Address; Albumins; Antibiotics; Bacteria; Bacterial Infections; Binding; Biochemical; Blood; Blood Circulation; CASP1 gene; CD14 gene; CD47 gene; CRISPR screen; Caspase; Cell Death; Cell Fractionation; Cell Wall; Cell membrane; Cell surface; Cells; Chronic; Cleaved cell; Communicable Diseases; Complement; Complex; Confocal Microscopy; Coupled; Cre-LoxP; Crystallization; Cytosol; Detection; Development; Disease; Distant; Electrons; Endosomes; Endothelial Cells; Event; Extracellular Space; Family; Flagellin; Flow Cytometry; Genetic Transcription; Germ Lines; HMGB1 gene; Host Defense; Human; Image; Immune; Immune response; Immunologic Surveillance; In Situ; In Vitro; Infection; Inflammasome; Inflammation; Inflammatory; Inflammatory Response; Innate Immune System; Integration Host Factors; Interleukin-1; Interleukin-1 beta; Interleukin-18; Knowledge; Leaky Gut; Life; Lipids; Literature; Location; Lytic; Mass Spectrum Analysis; Mediating; Membrane; Methods; Microscopic; Molecular; Multiprotein Complexes; Mus; Mutant Strains Mice; Myeloid Cells; Nucleic Acids; Outcome; Pathway interactions; Pattern; Pattern recognition receptor; Perforation; Pharmaceutical Preparations; Physiology; Play; Proteins; RNA; Regulation; Role; Sepsis; Signal Transduction; Structure; TLR4 gene; Toxin; Translational Activation; Uric Acid; VDAC1 gene; Vesicle; Virus; Work; base; cell type; cytokine; defined contribution; extracellular vesicles; immunoregulation; in vivo; insight; lipopolysaccharide-binding protein; microbial; pathogen; response; virtual

Inflammasome related caspases such as caspase-1, caspase-4, and caspase-11 are a subset of the caspase family specialized in executing a lytic form of cell death and IL-1 cytokine-based inflammatory response. The activation of these inflammatory caspases is strongly coupled to innate immune detection of infections and cellular perturbations via canonical and noncanonical inflammasomes. Inflammasomes are multiprotein complexes in the cytosol assembled in response to wide variety of pathogen-associated molecular patterns (PAMPs) including nucleic acids, toxins, flagellin, and cell wall components and endogenous danger signals (danger- associated molecular patterns, or DAMPs) such as ATP and uric acid crystals. The assembly of inflammasome complex leads to the autoproteolytic activation of inflammatory caspases. Enzymatically active versions of inflammatory caspases activate a pore forming protein called gasdermin D, which lyses the cells via plasma membrane perforation. Active caspase-1 also cleaves the inflammatory cytokines pro-IL-1β and pro-IL-18 into their active forms. Inflammatory caspases are important for initiating the inflammatory response against a wide variety of pathogens including bacteria and viruses. Inflammatory caspases also play crucial roles in sepsis, a major life-threatening condition associated with infections. Extracellular vesicles (EVs) are membrane-bound structures abundantly released by our living cells into the extracellular space. EVs are packaged with proteins, lipids, and RNAs, and EVs have emerged as a crucial mode of inter-cellular transfer of all three cargoes. EV-cargoes are functional and modulate the physiology of the recipient cells. However, the role of EVs in the inflammasome signaling is poorly understood. This proposal seeks to comprehensively address this critical knowledge gap in three specific aims. Aim 1 will characterize the impact of host-derived EVs on inflammatory caspase activation by PAMPs. Aims 2 and 3 will demonstrate the molecular and cellular mechanisms by which the host-derived EVs regulate PAMP-activation of inflammatory caspases. In summary, this proposal will reveal a new role for host-derived EVs in inflammasome responses in the context of host defense with great implications for human infectious diseases and sepsis.

炎症体相关的caspase，如caspase-1、caspase-4和caspase-11是 Caspase家族专门执行一种溶解形式的细胞死亡和基于IL-1的细胞因子 炎症反应。这些炎症性半胱氨酸酶的激活与 通过规范和非规范对感染和细胞扰动的先天免疫检测 炎症性小体。炎性小体是胞浆中的多蛋白复合体，组装在 对多种病原体相关分子模式(PAMP)的反应，包括核 酸、毒素、鞭毛和细胞壁成分以及内源性危险信号(危险- 相关的分子模式或阻尼物)，如三磷酸腺苷和尿酸结晶。组装的 炎症体复合体导致炎性半胱氨酸酶的自身蛋白分解激活。 具有酶活性的炎性半胱氨酸酶激活一种名为 Gasdermin D，通过质膜穿孔裂解细胞。激活的caspase-1也 将炎性细胞因子前-IL-1β和前-IL-18分解为其活性形式。炎症性 半胱氨酸天冬氨酸氨基转移酶对于启动对多种 病原体包括细菌和病毒。炎性半胱氨酸蛋白酶在脓毒症中也起着关键作用， 一种与感染相关的危及生命的主要疾病。细胞外小泡(EVS)是 我们的活细胞将大量的膜结合结构释放到细胞外空间。 电动汽车包装有蛋白质、脂质和RNA，电动汽车已经成为一种重要的 所有三种货物的细胞间转移。EV-Cargo具有功能，并调节生理 受体细胞的数量。然而，EVS在炎症体信号转导中的作用很差。 明白了。这项建议寻求在三个方面全面解决这一关键的知识差距 明确的目标。目标1将描述宿主来源的EVS对炎性caspase的影响 由PAMP激活。目标2和目标3将通过以下方式演示分子和细胞机制 宿主来源的EVS调节炎症caspase的PAMP激活。总而言之，这是 该提案将揭示宿主来源的EV在炎症体反应中的新角色 宿主防御对人类传染病和败血症具有重要意义。