Modulation of innate immune cellular homeostasis and inflammation resolution

项目摘要 由于有缺陷的稳态解决而导致的非解决性慢性炎症是 动脉粥样硬化是一种严重的心血管并发症，造成巨大的健康和经济损失。 来自PI小组和其他人的研究表明，缺乏有效的稳态负调节因子可能 是失控性炎症和慢性动脉粥样硬化发病机制的基础。PI的团队 确定IRAK-M（白细胞介素-1受体相关激酶M）是一种关键的负调节因子， 单核细胞炎症在分子水平上，PI观察到IRAK-M可以选择性抑制 通过抑制关键炎症转录因子如NFκB来活化单核细胞 IRF5在亚细胞水平，PI发现IRAK-M可以维持和恢复细胞内稳态 通过促进自噬的正确完成。在组织和病理生理水平，PI 报道，IRAK-M缺陷小鼠容易发展为动脉粥样硬化恶化，由于增强的 低级别炎性单核细胞向主动脉斑块的募集。单核细胞IRAK-M的水平是 在轻度炎症条件下的小鼠中显著降低。长期目标是定义小说 用于维持免疫环境的适当平衡和治疗动脉粥样硬化的治疗靶点 与慢性低度炎症有关。根据这些新的观察，目前的目标是 定义IRAK-M调节炎症极化的分子和细胞机制， 单核细胞在动脉粥样硬化发病过程中的作用。核心假设是IRAK-M缺乏可能 通过影响自噬完成， 炎症信号恶化有助于动脉粥样硬化的发病机制。为了验证这个假设， PI计划进行以下综合研究。目标1将检验IRAK-M可能维持 单核细胞稳态通过负调节TRAF 6-p62介导的炎症信号通路。 目的2将验证IRAK-M可能通过促进自噬来维持单核细胞稳态的假设 建成目的3将检验IRAK-M缺陷引起的单核细胞极化在单核细胞分化中起关键作用的假设。 在动脉粥样硬化恶化期间。该项目的完成将定义新的分子和细胞 导致动脉粥样硬化恶化的炎症消退缺陷的机制， 开发治疗与低度炎症相关的动脉粥样硬化的治疗策略。

Project summary Non-resolving chronic inflammation due to defective homeostatic resolution underlies the pathogenesis of atherosclerosis, a significant cardiovascular complication that imposes enormous health and economic tolls. Studies from the PI’s group and others indicate that the lack of effective homeostatic negative regulators may underlie the run-away inflammation and the pathogenesis of chronic atherosclerosis. The PI’s group has identified that IRAK-M (interleukin-1 receptor associated kinase M) is one of the key negative regulators of monocyte inflammation. At the molecular level, the PI observed that IRAK-M may selectively suppress inflammatory activation of monocytes through suppressing key inflammatory transcription factors such as NFκB and IRF5. At the sub-cellular level, the PI discovered that IRAK-M may maintain and restore cellular homeostasis through facilitating the proper completion of autophagy. At the tissue and pathophysiological level, the PI reported that IRAK-M deficient mice are prone to develop aggravated atherosclerosis, due to enhanced recruitment of low-grade inflammatory monocytes to the aortic plaque. The levels of monocyte IRAK-M are significantly reduced in mice under low-grade inflammatory conditions. The long-term goal is to define novel therapeutic targets for maintaining a proper balance of immune environment and treating atherosclerosis associated with chronic low-grade inflammation. Based on these novel observations, the current objective is to define molecular and cellular mechanisms by which IRAK-M modulates the inflammatory polarization of monocytes during the pathogenesis of atherosclerosis. The central hypothesis is that IRAK-M deficiency may polarize a non-resolving pro-inflammatory monocyte state through affecting autophagy completion and inflammatory signaling exacerbation conducive to the pathogenesis of atherosclerosis. To test this hypothesis, the PI plans to perform the following integrated studies. Aim 1 will test the hypothesis that IRAK-M may maintain monocyte homeostasis through negatively regulating TRAF6-p62 mediated inflammatory signaling pathways. Aim 2 will test the hypothesis that IRAK-M may maintain monocyte homeostasis through facilitating autophagy completion. Aim 3 will test the hypothesis that monocyte polarization due to IRAK-M deficiency plays a key role during the exacerbation of atherosclerosis. Completion of this project will define novel molecular and cellular mechanisms responsible for the defective inflammation resolution in exacerbated atherosclerosis, and facilitate the development of therapeutic strategies in treating atherosclerosis associated with low-grade inflammation.