Novel Mechanisms of Cytokine Storage and Secretion

导言：我的研究集中在免疫系统中关键的细胞间通讯因子的生物学上。这些传播者，细胞因子，是在免疫细胞之间传递信号的小蛋白，协调协调有效的免疫。细胞因子包括从各种产生细胞释放的一系列蛋白质，以诱导许多不同的生物效应。通常，激活的刺激会诱导细胞因子基因表达，并随后从免疫细胞中分泌新形成的细胞因子。有趣的是，有一种很少被描述的现象，即某些细胞因子可以储存在免疫细胞内，预先形成，允许快速分泌，而不需要从头合成蛋白质。虽然许多经典的“颗粒状”免疫细胞有能力在其不同的颗粒中储存预先形成的细胞因子，但对单核细胞和巨噬细胞的这种能力知之甚少。我们试图通过阐明单核/巨噬细胞亚群中预先形成的细胞因子的分布，识别独特的亚细胞储存隔间，以及分泌的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一个子集可以预先形成并储存在独特的亚细胞室中，支持对炎症刺激的快速和强大的免疫反应。目的：1.从单核细胞和巨噬细胞亚群中鉴定细胞因子的分泌谱(储存的细胞因子与去新生产生的细胞因子)。2.研究细胞因子的储存区及其分子机制。3.描述诱导从头合成细胞因子的独特刺激与快速释放预先形成的细胞因子的刺激。意义：这项研究填补了细胞因子生物学知识的一个重要空白，特别是单核/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细胞因子储存的现象，但据我们所知，在单核/巨噬细胞中只有一项研究报道。由于这些细胞被认为是先天免疫的哨兵，它们在协调炎症反应以有效清除感染方面具有主要作用。因此，这项工作描述了免疫反应是如何从细胞激活和细胞因子分泌的最早阶段开始协调的，并将加深我们对细胞因子介导的免疫的理解。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，这些培训机会可以翻译到不同的研究领域和职业道路。

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.