PPARγ在慢性应激促巨噬细胞M2型极化中的关键作用及机制研究

Previous studies, including ours, have shown that chronic stress such as social isolation plays a critical role in the procession of breast cancer. Chronic stress increased NE and E released from the sympathetic nervous system (SNS) and/or the adrenal medulla that, by activating β2 receptors on the macrophages, promoted macrophages to M2 phenotype and thus led to the progression of breast cancer. However, the underlying molecular mechanism is unclear. Our whole-genome microarray data indicated that PPARγ acted as a major player in the progression of breast cancer induced by chronic stress. Q-PCR, Western blot and FACS results confirmed that expression of PPARγ and M2-related molecules such as CD163 and MR enchanced significantly under chronic stress or NE treatment. Therefore, we hypothesized that PPARγ and its related up- and down-stream signaling pathways may play a crucial role in promoting M2 polarization of macrophages induced by chronic stress. Our aims are as follows: 1) To confirm that chronic stress and activation of adrenergic systems promote the expression of PPARγ on macrophages; 2) To investigate the role of PPARγ in adrenergic systems promoting the polarization of macrophages toward M2 and hence the progression of breast cancer; 3) To reveal the role of CREB/PPARγ/NOX4 /ROS signaling pathway in promoting macrophages polarized to M2 phenotype..This study will confirm that the adrenergic system, a key player in the neuroendocrine immune networks, plays an important regulatory role in the tumor microenvironment. Our study may provide new targets for tumor prevention and treatment that is associated with the perspective of social psychology.

综合文献报道及我们的前期研究显示社交孤立等慢性应激通过交感神经系统（SNS）和肾上腺髓质释放NE和E作用于巨噬细胞上β2受体促进其向M2型极化从而发挥促瘤效应，但机制不清。前期基因芯片结果显示其可能主要由PPARγ信号通路介导；而且慢性应激或NE处理后瘤内PPARγ及M2型相关分子表达均明显增加。因此本课题拟通过系统研究来证明PPARγ在慢性应激后促巨噬细胞M2型极化中的关键作用及其上下游信号通路。主要研究工作如下：1)证实慢性应激及肾上腺素能系统（AS）促进巨噬细胞上PPARγ的表达；2)阐述PPARγ在肾上腺素能系统促巨噬细胞向M2型极化进而促瘤中的作用；3)揭示CREB/PPARγ/NOX4/ROS信号通路在PPARγ促巨噬细胞向M2型极化中的作用。本研究将从心理应激角度证实神经内分泌免疫网络中的关键：AS对肿瘤微环境的重要调节作用并揭示其机制，以期为肿瘤防治提供新靶点新手段。

本项目探讨了PPARγ在慢性应激后巨噬细胞M2型极化中的关键作用及其上下游信号通路。主要研究工作如下：1)证实慢性应激及肾上腺素能系统（AS）促进巨噬细胞上PPARγ的表达；2)阐述PPARγ在肾上腺素能系统促巨噬细胞向M2型极化进而促瘤中的作用；3)揭示CREB/PPARγ/NOX4/ROS信号通路在PPARγ促巨噬细胞向M2型极化中的作用。研究结果发现在慢性应激激活肾上腺素能β2受体（β2AR），进而通过腺苷酸环化酶（AC）信号通路促进PPARγ的表达，导致巨噬细胞RAW264.7细胞向M2型极化，最终加快乳腺癌进展。在小鼠动物实验上，我们也发现了同样的效应。β2AR 抑制剂ICI118551和/或PPARγ抑制剂GW9662可抑制慢性应激及其相关激素尤其是去甲肾上腺素促巨噬细胞向M2型极化的效应。另外，NOX4/ROS信号通路介导了PPARγ促进巨噬细胞向M2型极化的作用。本研究证实神经内分泌免疫网络中的关键角色肾上腺能系统对肿瘤微环境的重要调节作用，并揭示了其作用机制，为乳腺癌的防治提供心理社会因素方面的理论指导，为肿瘤防治提供新靶点新手段。