Novel Mechanisms of Cytokine Storage and Secretion

细胞因子储存和分泌的新机制

• 批准号: RGPIN-2019-06442
• 负责人: Guzzo, Christina
• 金额: $ 2.7万
• 依托单位: University of Toronto
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=744898
• 关键词: Novel; Mechanisms; Cytokine; Storage; Secretion

INTRODUCTION: My research is centered on the biology of key cell-to-cell communicators in the immune system. These communicators, cytokines, are small proteins which convey signals between immune cells, working in harmony to coordinate effective immunity. Cytokines include a broad range of proteins that are released from a variety of producer cells to induce many different biological effects. Typically, an activating stimulus will induce cytokine gene expression and subsequent secretion of newly formed cytokines from immune cells. Interestingly, there is a poorly described phenomenon in which certain cytokines can be stored, pre-formed inside immune cells, permitting rapid secretion without requiring de novo protein synthesis. While many classical `granular' immune cells have a documented capacity to store pre-formed cytokines within their various granules, very little is known about this capacity in monocytes and macrophages. We seek to address this void by elucidating the profile of pre-formed cytokines in monocyte/macrophage subsets, identifying the unique subcellular compartments of storage, and signaling pathways to secretion. This work is relevant to better establish fundamental mechanisms of inflammatory responses and may suggest new molecular targets for immunomodulation. HYPOTHESIS: We hypothesize that a subset of cytokines can be pre-formed and stored intracellularly in unique subcellular compartments, supporting rapid and robust immune responses to inflammatory stimuli. AIMS: 1.To identify the cytokine secretion profiles (stored cytokines vs de novo-produced cytokines) from monocyte and macrophage subsets. 2.To characterize the cytokine storage compartments and the molecular mechanisms of storage. 3.To delineate the unique stimuli that induce de novo cytokine synthesis versus rapid release of pre-formed cytokines. SIGNIFICANCE: This research fills an important gap in knowledge on cytokine biology, particularly in cytokine storage and secretion within monocytes/macrophages. While the phenomenon of pre-formed cytokine storage has been described in traditional granulocytes, to our knowledge, only one study has ever been reported in monocytes/macrophages. Since these cells are regarded in sentinels in innate immunity, they have primary roles in coordinating inflammatory responses to effectively clear infection. Thus, this work characterizes how immune responses are orchestrated from the earliest stages of cell activation and cytokine secretion, and will enhance our understanding of cytokine-mediated immunity. This research challenges the dogma of how innate immune responses are coordinated and may lead to the identification of novel triggers for rapid immunity. Additionally, this research program will provide training opportunities for HQP that are translatable to a diverse range of research fields and career paths.

简介：我的研究集中在免疫系统中关键细胞间通讯者的生物学。这些通讯者，细胞因子，是在免疫细胞之间传递信号的小蛋白质，协调工作以协调有效的免疫。细胞因子包括从各种生产细胞释放的广泛的蛋白质，以诱导许多不同的生物学效应。通常，激活刺激将诱导细胞因子基因表达和随后从免疫细胞分泌新形成的细胞因子。有趣的是，存在一种描述不多的现象，其中某些细胞因子可以在免疫细胞内储存、预先形成，允许快速分泌而不需要从头蛋白质合成。虽然许多经典的“颗粒”免疫细胞具有记录的在其各种颗粒内储存预先形成的细胞因子的能力，但对单核细胞和巨噬细胞中的这种能力知之甚少。我们试图通过阐明单核细胞/巨噬细胞亚群中预先形成的细胞因子的概况，确定独特的亚细胞储存区室和分泌信号通路来解决这一空白。这项工作与更好地建立炎症反应的基本机制有关，并可能为免疫调节提供新的分子靶点。假设：我们假设细胞因子的子集可以预先形成并储存在细胞内独特的亚细胞区室中，支持对炎症刺激的快速和强大的免疫应答。目的：1.鉴定单核细胞和巨噬细胞亚群的细胞因子分泌谱（储存的细胞因子与新产生的细胞因子）。2.研究细胞因子的储存区及其储存的分子机制。3.描述诱导细胞因子重新合成与快速释放的独特刺激。重要性：这项研究填补了细胞因子生物学知识的重要空白，特别是单核细胞/巨噬细胞内细胞因子的储存和分泌。虽然在传统的粒细胞中已经描述了预形成的细胞因子储存的现象，但据我们所知，在单核细胞/巨噬细胞中仅报道了一项研究。由于这些细胞被认为是先天免疫中的哨兵，它们在协调炎症反应以有效清除感染中起主要作用。因此，这项工作的特点是如何从细胞活化和细胞因子分泌的最早阶段的免疫反应是精心策划的，并将提高我们的理解，姜黄素介导的免疫。这项研究挑战了先天免疫反应如何协调的教条，并可能导致识别快速免疫的新触发因素。此外，该研究计划将为HQP提供培训机会，这些机会可以转化为各种研究领域和职业道路。