脂肪组织巨噬细胞exosome-miRNAs介导组织间crosstalk在运动拮抗PM2.5致胰岛素抵抗中的作用及机制研究

Chronic exposure to inhalable particulate matter (PM) can increase the risk of insulin resistance (IR) and other diseases. We have found that PM2.5 caused respiratory inflammation in initial target organs, and promoted macrophage recruitment into adipose tissue, then triggered cascade reaction and result in systemic, chronic and low-grade inflammation. Regular aerobic exercise can resist the above process induce by PM2.5, which involved in the exosome and the balance of intra- and extra- cellular HSP70. It is reported that adipose tissue macrophage(ATM)-derived exosomal miRNAs can modulate in vivo and in vitro insulin sensitivity. Does the anti-inflammatory effect of exercise involve in the inter-tissue crosstalking mediated by ATM-exosome’s microRNAs, to influence metabolic diseases (such as IR)? In this study, chronic aerobic exercise model and PM2.5-induced IR model of mice are established, and ATM of two types of model mice are separated out. Then the ATM-derived exosome are extracted and cross injected in vivo. The effect of ATM-derived exosome from two types of model mice on glucose metabolism of each other mice are observed. The expression profiles of microRNAs in ATM-exosome from exercise mice and IR mice induced by PM2.5 are quantitatively analyzed to find out the key molecule of exercise to cure IR induced by PM2.5. Experiments of in vivo and vitro (hepatic, adipose and muscular cell) are performed to verify the function of microRNAs and its mechanism of inter-tissue crosstalking. This study is helpful to explore the comprehensive effects of environment and exercise on health, and to reveal the crosstalking’s mechanism of exercise in the modulation of inflammation-related diseases induced by air pollution.

大气颗粒物暴露增加胰岛素抵抗（IR）等多种疾病的风险。我们前期发现PM2.5致初始靶器官呼吸道炎症，激活单核巨噬细胞归巢脂肪组织，经炎症级联反应导致机体慢性低度炎症，而运动拮抗此过程，其机制涉及外泌体介导的细胞内外HSP70平衡。有学者发现脂肪组织巨噬细胞（ATM）外泌体内miRNA可调节多种组织的胰岛素敏感性。因此，运动的抗炎效应是否涉及ATM外泌体miRNA介导的组织间对话，进而防治IR等代谢性疾病？本研究分别建立小鼠长期有氧运动模型和PM2.5诱导的IR模型，提取模型小鼠ATM外泌体，在体交叉注射，观察两种来源外泌体对对方小鼠糖代谢的影响。通过两种来源的外泌体miRNA表达谱差异分析，寻找运动防治PM2.5致IR的关键分子。在体及（肝、脂肪、骨骼肌）细胞实验来验证miRNA的功能及组织间对话机制。探讨环境和运动对健康的综合影响，揭示运动在防治空气污染所致炎症相关性疾病中的对话机制。

空气污染已成为世界的主要公共卫生问题，其中可吸入颗粒物对机体健康危害广泛。大量证据表明，PM2.5可致初始靶器官呼吸道炎症，激活单核巨噬细胞归巢脂肪组织，经炎症级联反应导致机体慢性低度炎症，增加胰岛素抵抗（IR）等多种疾病的风险。运动已成为一种增强免疫力，预防疾病发生，改善代谢性疾病发展的有效干预手段。而运动的抗炎效应是否涉及颗粒物所致的初始靶器官呼吸道炎症及脂肪组织慢性低度炎症尚不可知。运动是否参与调控外泌体介导细胞间的交互效应，进而防治呼吸道损伤及IR等疾病亟待研究。基于此，本研究采用浓缩富集全身暴露系统模拟大气暴露的真实环境，以炎症反应及通路为靶点，通过探究长期有氧运动对慢性PM2.5暴露致小鼠胰岛素抵抗的治疗效果及其脂肪组织间充质干细胞外泌体与巨噬细胞之间的交互效应等相关机制。有氧运动对亚急性PM2.5暴露致肺损伤的保护效应及其抑制PM2.5所致的肺部炎症的关键靶点。研究发现：长期有规律的有氧运动可在一定程度上改善PM2.5污染所致的IR，可经由脂肪组织间充质干细胞外泌体内miRNAs介导与巨噬细胞之间发生交互效应，进而改善长期PM2.5暴露所导致的胰岛素抵抗。亚急性PM2.5暴露导致的肺脏损伤，GSK3β可能是运动保护PM2.5所致的肺部炎症的关键靶点之一。本研究可在大气环境质量未能得到有效控制的情况下，如何科学开展运动促进健康提供相关实验依据。