IL-17介导巨噬细胞极化对BPA诱导肥胖中脂肪组织炎症的调控及机制研究

Bisphenol A (BPA) is a ubiquitous environmental endocrine disrupting chemical. Recently, BPA -induced obesity attracted widespread attentions. However, the underlying mechanism has not yet been fully elucidated. Literature suggest that regulate the polarization of adipose tissue macrophages (ATMs) , the critical factor in development of obesity, can change the outcomes of obesity. Our previous studies have shown that BPA can promote macrophage polarization to the M1 type in vitro, as well as maternal exposure to low-dose BPA by drinking water during pregnancy and lactation, can lead to elevate serum IL-17 levels in offspring mice. On the basis of these results, this study intends to explore the activation of IL-17+ cells in adipose tissue, increase in IL-17 level, then mediate ATMs shift to M1-type polarization, aggravate the accumulation of macrophage in adipose tissue, contribute to adipose tissue inflammation in BPA-induced obesity, using IL-17 neutralizing antibody, IL-17 knockout mice and IL-17+ cells adoptive transfer experiments. In vitro, we cocultre various combinations of adipose tissue, IL-17+ cells and macrophages, to further explore the cellular interplay via which inflammation develops in obese adipose tissue of BPA-induced obesity.As well as, investigate the molecular mechanisms of IL-17 mediate the polarization of ATMs using RNA interference. The results of this study provide a new theoretical basis to elucidate the pathogenesis and regulator mechanisms of obesity induced by BPA exposure, and provide a new ideas for the prevention of health hazards of environmental BPA exposure.

双酚A（BPA）暴露诱导肥胖受到广泛关注，但其机制目前仍未完全阐明。文献提示调控肥胖发展的关键环节脂肪组织巨噬细胞（ATMs）极化可改变肥胖中脂肪组织炎症状态。本研究拟在课题组前期发现BPA促进巨噬细胞向M1型极化，及围生期BPA暴露引起子代血清IL-17水平升高的基础上，用IL-17中和抗体、IL-17基因敲除小鼠和IL-17+细胞过继转移，探讨脂肪组织激活IL-17+细胞，上调IL-17介导ATMs向M1型极化，加重脂肪组织ATMs聚集，促进脂肪组织炎症在BPA诱导肥胖中的作用；通过体外共培养实验验证BPA诱导肥胖中，BPA诱导脂肪细胞分化，脂肪组织脂肪细胞、IL-17+细胞和巨噬细胞相互作用，促进组织炎症，并结合RNA干扰实验深入研究IL-17调控ATMs极化的分子机制。本研究为阐明环境BPA暴露诱导肥胖的发病及调控机制提供新的科学依据，并为防治环境BPA暴露的健康危害提供新的思路。

肥胖可引起机体一序列并发症，已成为一个日益严重的全球性公共卫生问题，预防和控制肥胖及其并发症已成为当前公共卫生领域刻不容缓的任务，增加对肥胖病因及发病机制的了解具有重要的现实意义。越来越多的证据表明，环境内分泌干扰物（EDCs）具有致肥胖作用。双酚A（BPA）是最常见的EDCs，属世界上高产量化学物之一，在工业生产和日常生活中人类可广泛暴露于BPA。流行病学研究表明BPA属于“环境致肥胖因子”，可诱导肥胖，但其机制目前仍未完全阐明。文献提示机体在肥胖情况下，脂肪组织巨噬细胞（ATMs）在脂肪组织炎症因子作用下其表型可发生偏向M1型极化改变，并分泌大量促炎因子促进ATMs在脂肪组织聚集，加重脂肪组织炎症。本项目通过动物实验显示环境相当剂量BPA暴露可增加小鼠体重和附睾脂肪垫质量，并提高机体瘦素水平，而且在高脂饮食喂养小鼠中效果更显著，表明BPA可诱导肥胖，且BPA与高脂饮食具有协同作用；在BPA诱导肥胖中，脂肪组织中Th17细胞被激活，分泌大量炎性细胞因子IL-17，介导ATMs偏向M1型极化并在脂肪组织大量聚集，从而促进脂肪组织炎症。项目还利用体外研究揭示了BPA可诱导小鼠3T3-L1前脂肪细胞向脂肪细胞分化，并产生大量脂肪因子和炎症细胞因子，PPARγ可通过C/EBP调控BPA诱导的小鼠前脂肪细胞分化；另外，BPA还可诱导体外培养的小鼠腹腔巨噬细胞向M1型极化，而抑制向M2型极化，IRF5在BPA诱导M1型极化中发挥重要作用的机制。本项目的研究结果丰富了环境致肥胖因子诱导肥胖的发病及调控机制，为环境BPA暴露的健康危害防治提供新的思路。