Modulation of innate immune cellular homeostasis and inflammation resolution

项目总结 由于体内平衡分解缺陷而导致的慢性炎症无法消退是其发病机制的基础 动脉粥样硬化，一种重要的心血管并发症，会造成巨大的健康和经济损失。 PI的研究小组和其他人的研究表明，缺乏有效的体内平衡负调控可能 炎症失控和慢性动脉粥样硬化的发病机制。少年警卫队的小组已经 IRAK-M(白细胞介素1受体相关激酶M)是一种重要的负性调节因子。 单核细胞炎症。在分子水平上，PI观察到IRAK-M可能选择性地抑制 抑制核因子κB等关键炎性转录因子对单核细胞的炎症激活作用 和IRF5。在亚细胞水平上，PI发现IRAK-M可能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上，猪 报道称，IRAK-M基因缺陷的小鼠容易患上动脉粥样硬化加重，这是由于增强 低级别炎性单核细胞重新聚集到主动脉斑块。单核细胞IRAK-M水平为 在小鼠轻度炎症条件下显著降低。其长期目标是定义小说 维持免疫环境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。基于这些新的观察结果，目前的目标是 明确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中的作用。中心假说是IRAK-M缺乏可能 通过影响自噬完成而极化非分解的促炎性单核细胞状态 炎症信号的加剧有利于动脉粥样硬化的发病。为了检验这一假设， 国际和平研究所计划进行以下综合研究。目标1将检验伊拉克-M可能维持的假设 通过负调控TRAF6-p62介导的炎症信号通路实现单核细胞动态平衡。 目标2将验证IRAK-M可能通过促进自噬来维持单核细胞动态平衡的假设 完成了。目标3将检验IRAK-M缺乏引起的单核细胞极化起关键作用的假设 在动脉粥样硬化恶化的过程中。该项目的完成将定义新的分子和细胞 动脉粥样硬化加重中炎症分解缺陷的机制及促进 与低度炎症相关的动脉粥样硬化治疗策略的发展。

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.