Mechanisms of IL-1B secretion during microbial infection

微生物感染过程中IL-1B的分泌机制

• 批准号: 8832921
• 负责人: Brooke Ann Napier
• 金额: $ 5.24万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-02-01 至 2018-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8832921
• 关键词: Anti-Inflammatory Agents; Anti-inflammatory; Bacteria; Binding; Bone Marrow; Candidate Disease Gene; Caspase-1; Cell secretion; Cells; Chronic; Data Set; Development; Disease; Ensure; Event; Exocytosis; Future; Gene Targeting; Genes; Goals; Immune; Immune response; Individual; Infection; Inflammation; Inflammatory; Integration Host Factors; Interleukin-1; Interleukin-1 Receptors; Interleukins; Lead; Mediator of activation protein; Messenger RNA; Molecular; Mus; Pathway interactions; Predisposition; Process; Production; Proteins; Role; Salmonella typhimurium; Signal Pathway; Signal Transduction; Small Interfering RNA; Sorting - Cell Movement; Therapeutic; Transfection; Work; adaptive immunity; antimicrobial; base; cytokine; drug development; extracellular; genome-wide; interest; loss of function; mRNA Expression; macrophage; microbial; pathogen; public health relevance; response; secretion process; secretory protein; therapeutic target; trafficking

 DESCRIPTION (provided by applicant): Interleukin-1β (IL-1β) is a proinflammatory cytokine that has been the focus of much interest due to its importance in controlling inflammation during microbial infection and chronic inflammatory disease. During microbial infections, secretion of IL-1β is an essential step for the innate immune defense and modulation of adaptive immune responses. After secretion into the extracellular milieu, IL-1β can bind to interleukin-1 receptor (IL-1R) and induce a signaling cascade important for the release of other proinflammatory cytokines and induction of a Th17 bias in the adaptive immune response. All of these events are integral for rapid clearance of infection and host susceptibility to infection. Despite intensive study on the production and processing of IL-1β, the mechanism of active IL-1β secretion from innate immune cells still remains unsolved. Many proinflammatory cytokines are secreted through classical protein secretory pathway; however, IL-1β lacks the proper signal to be trafficked through this pathway. Thus, it has been hypothesized that IL-1β is secreted via a non-classical secretory pathway. Recent studies have suggested that IL-1β release in response to intracellular bacteria may rely on a variety of non-classical secretory pathways, including: lysosomal exocytosis, microvesicles, and exosomal exocytosis. However, none of these studies have been conclusive. The intracellular bacterial pathogen Salmonella typhimurium induces robust IL-1β secretion after inflammasome activation in macrophages. The release of IL-1β from infected cells is imperative for control and clearance of the infection; however, the mechanism of secretion is not known. Thus, we aim to identify new host factors involved in secretion of IL-1β in response to S. typhimurium infection. We hypothesize that multiple unidentified proteins are required for non-classical secretion of IL-1β during microbial infection. This work will lead to a better understanding of how IL-1β secretion and trafficking is regulated during microbial infections and other chronic inflammatory diseases. Additionally, the results of these studies will work towards identifying ideal therapeutic targets for future anti-inflammatory drug development.

 描述（由申请人提供）：白细胞介素-1 β（IL-1β）是一种促炎细胞因子，由于其在微生物感染和慢性炎性疾病期间控制炎症的重要性，一直是人们关注的焦点。在微生物感染期间，IL-1β的分泌是先天免疫防御和调节适应性免疫应答的重要步骤。IL-1β分泌到细胞外环境后，可与IL-1受体结合 （IL-1 R）并诱导对于释放其它促炎细胞因子和诱导适应性免疫应答中的Th 17偏向重要的信号级联。所有这些事件对于快速清除感染和宿主对感染的易感性是不可或缺的。尽管对IL-1β的产生和加工进行了深入的研究，但先天免疫细胞主动分泌IL-1β的机制仍然没有得到解决。许多促炎细胞因子通过经典的蛋白质分泌途径分泌;然而，IL-1β缺乏通过该途径运输的适当信号。因此，假设IL-1β通过非经典分泌途径分泌。最近的研究表明，响应于细胞内细菌的IL-1β释放可能依赖于多种非经典分泌途径，包括：溶酶体胞吐、微泡和外泌体胞吐。然而，这些研究都不是结论性的。细胞内细菌病原体鼠伤寒沙门氏菌在巨噬细胞中的炎性体活化后诱导稳健的IL-1β分泌。从感染细胞释放IL-1β对于控制和清除感染至关重要;然而，分泌机制尚不清楚。因此，我们的目的是确定新的宿主因子参与分泌IL-1β响应S。鼠伤寒感染我们假设在微生物感染期间，IL-1β的非经典分泌需要多种未鉴定的蛋白质。这项工作将导致 更好地了解在微生物感染和其他慢性炎症性疾病期间IL-1β分泌和运输是如何调节的。此外，这些研究的结果将 致力于为未来的抗炎药物开发确定理想的治疗靶点。