A novel mechanism for NLRP3 inflammasome activation in human macrophages

人类巨噬细胞中 NLRP3 炎症小体激活的新机制

基本信息

  • 批准号:
    10343393
  • 负责人:
  • 金额:
    $ 76.57万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2022
  • 资助国家:
    美国
  • 起止时间:
    2022-06-16 至 2027-05-31
  • 项目状态:
    未结题

项目摘要

Infections and cellular stress can trigger cytoplasmic pattern recognition receptors to assemble an inflammasome complex, which promotes the release of the inflammatory cytokines IL-1β, IL-18 and the induction of pyroptotic cell death. Inflammasome responses are also perpetuated and propagated to bystander cells. Ultimately, this response contributes to pathogen clearance and wound healing. However, excessive inflammasome activation can contribute to- or cause debilitating symptoms associated with inflammatory diseases. Particularly, the NLRP3 inflammasome has been directly linked to numerous diseases. It has a unique position by not only sensing infections, but also cellular stress and tissue damage. Even though the NLRP3 inflammasome is of utmost importance for balancing between homeostasis and disease, and is therefore a prime target for novel treatment strategies, the underlying molecular mechanisms, particularly in human macrophages, are still poorly understood. There are numerous human inflammasome components that are absent in mice and their functional contribution to human health and disease are even less well understood than the more conserved factors. Elucidating unique human responses is the main focus of our lab. Innate immune receptor oligomerization initiates inflammatory host responses, including inflammasome activation. The research outlined in this proposal is designed to mechanistically unravel a novel NLRP3 inflammasome activation concept in human macrophages. We discovered a novel NLRP3 inflammasome component in human macrophages, which interacts with NLRP3, but is absent from mice and our preliminary studies revealed that NLRP3 requires this co-sensor for oligomerization as well as for recruiting the inflammasome adaptor, ASC. Furthermore, NLRP3 and its co-sensor are necessary for efficiently nucleating ASC polymerization and caspase-1 activation. Knock out of the co-sensor phenocopies NLRP3 knock out in human macrophages. Significantly, it is absolutely necessary for cytokine release driven by NLRP3 mutations that cause Cryopyrin-Associated Periodic Syndrome (CAPS). We propose two specific aims that investigate the mechanism and function of the co-sensor in NLRP3 inflammasome assembly and activation in macrophages, as well as the molecular events that enable this co-sensor to promote NLRP3 inflammasome activation. We will utilize CRISPR/Cas9 knock out and restored expression of wild type and mutant co-sensor proteins and a humanized mouse expressing the human co-sensor for studying its function in vivo. We expect that our research will uncover novel molecular mechanisms that not only change our current understanding of control mechanisms that prevent inappropriate NLRP3 inflammasome activation for maintaining homeostasis and human health, but also NLRP3-driven pathologies in inflammatory diseases. The outcomes of our study will move the field forward and will be highly significant for understanding disease pathologies and for the development of novel therapies that benefit patients and positively affect human health.
感染和细胞应激可以触发细胞质模式识别受体组装 炎症小体复合物,促进炎症细胞因子 IL-1β、IL-18 和 诱导焦亡细胞死亡。炎症反应也会持续存在并传播给旁观者 细胞。最终,这种反应有助于病原体清除和伤口愈合。然而,过度 炎症小体激活可能导致或导致与炎症相关的衰弱症状 疾病。特别是,NLRP3 炎症小体与许多疾病直接相关。它有一个 其独特的地位不仅可以感知感染,还可以感知细胞压力和组织损伤。尽管 NLRP3 炎症小体对于体内平衡和疾病之间的平衡至关重要,并且 因此,潜在的分子机制是新治疗策略的主要目标,特别是在 人类巨噬细胞仍然知之甚少。有许多人类炎症小体成分 在小鼠中不存在,并且它们对人类健康和疾病的功能贡献甚至更不为人所知 比更保守的因子。阐明人类独特的反应是我们实验室的主要重点。 先天免疫受体寡聚化启动炎症宿主反应,包括炎症小体 激活。本提案中概述的研究旨在机械地揭示一种新颖的 NLRP3 人类巨噬细胞中炎症小体激活的概念。我们发现了一种新的 NLRP3 炎性小体 人类巨噬细胞中的一个成分,它与 NLRP3 相互作用,但在小鼠中不存在,我们的初步研究 研究表明,NLRP3 需要这种辅助传感器进行寡聚化以及招募 炎性小体接头,ASC。此外,NLRP3 及其辅助传感器对于有效成核是必要的 ASC 聚合和 caspase-1 激活。敲除辅助传感器表型 NLRP3 敲除 人类巨噬细胞。值得注意的是,NLRP3 突变驱动的细胞因子释放是绝对必要的 导致冷热蛋白相关周期性综合症 (CAPS) 的原因。我们提出了两个具体目标来调查 NLRP3炎症小体组装和激活中辅助传感器的机制和功能 巨噬细胞,以及使该辅助传感器能够促进 NLRP3 炎症小体的分子事件 激活。我们将利用 CRISPR/Cas9 敲除并恢复野生型和突变型共传感器的表达 蛋白质和表达人类辅助传感器的人源化小鼠,用于研究其体内功能。 我们期望我们的研究将揭示新的分子机制,不仅改变我们当前的 了解防止 NLRP3 炎症小体不适当激活的控制机制 维持体内平衡和人类健康,以及 NLRP3 驱动的炎症性疾病病理。 我们的研究结果将推动该领域向前发展,对于理解疾病具有非常重要的意义 病理学并开发有利于患者并对人类健康产生积极影响的新疗法。

项目成果

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Andrea Dorfleutner其他文献

Andrea Dorfleutner的其他文献

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{{ truncateString('Andrea Dorfleutner', 18)}}的其他基金

A novel mechanism for NLRP3 inflammasome activation in human macrophages
人类巨噬细胞中 NLRP3 炎症小体激活的新机制
  • 批准号:
    10646142
  • 财政年份:
    2022
  • 资助金额:
    $ 76.57万
  • 项目类别:
A novel essential inflammasome component propagating inflammatory responses
传播炎症反应的新型重要炎症体成分
  • 批准号:
    9884718
  • 财政年份:
    2019
  • 资助金额:
    $ 76.57万
  • 项目类别:
A novel essential inflammasome component propagating inflammatory responses
传播炎症反应的新型重要炎症体成分
  • 批准号:
    10577887
  • 财政年份:
    2019
  • 资助金额:
    $ 76.57万
  • 项目类别:
A novel essential inflammasome component propagating inflammatory responses
传播炎症反应的新型重要炎症体成分
  • 批准号:
    10341160
  • 财政年份:
    2019
  • 资助金额:
    $ 76.57万
  • 项目类别:
CARD-only protein regulation of cytosolic Pattern Recognition Receptor signaling
细胞质模式识别受体信号传导的仅 CARD 蛋白调节
  • 批准号:
    10415886
  • 财政年份:
    2018
  • 资助金额:
    $ 76.57万
  • 项目类别:
CARD-only protein regulation of cytosolic Pattern Recognition Receptor signaling
细胞质模式识别受体信号传导的仅 CARD 蛋白调节
  • 批准号:
    10176387
  • 财政年份:
    2018
  • 资助金额:
    $ 76.57万
  • 项目类别:
Inflammasome adaptor and effectors in Cryopyrinopathies and crystal arthropathies
冷热蛋白病和晶体关节病中的炎性小体接头和效应器
  • 批准号:
    8891653
  • 财政年份:
    2015
  • 资助金额:
    $ 76.57万
  • 项目类别:
Molecular Regulation of Systemic Inflammation
全身炎症的分子调节
  • 批准号:
    9888298
  • 财政年份:
    2015
  • 资助金额:
    $ 76.57万
  • 项目类别:
Inflammasome adaptor and effectors in Cryopyrinopathies and crystal arthropathies
冷热蛋白病和晶体关节病中的炎性小体接头和效应器
  • 批准号:
    9040884
  • 财政年份:
    2015
  • 资助金额:
    $ 76.57万
  • 项目类别:
Inflammasome adaptor and effectors in Cryopyrinopathies and crystal arthropathies
冷热蛋白病和晶体关节病中的炎性小体接头和效应器
  • 批准号:
    9246983
  • 财政年份:
    2015
  • 资助金额:
    $ 76.57万
  • 项目类别:

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