Novel Mechanisms of Cytokine Storage and Secretion

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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.