慢性心理应激对髓系来源抑制细胞的影响与机制

With China's rapid development, people in China are facing more and more psychological problems. It has been demonstrated that persistent stress and depression, which leads to continuously elevated levels of stress hormones, might eventually compromise host defenses against bacterial or viral infection while increasing the reoccurance of autoimmunity and the incidence of malignancy/ metastasis. Even though the molecular mechanisms by which chronic psychological stress inhibits the effector subsets in the immune system have been partially disclosed, it remains unknown whether chronic psychological stress also affects the regulatory subsets and if yes, what are the underlying mechanisms. Recently, myeloid-derived suppressor cells (MDSC) have received considerable attention because they potently perturb both innate and adaptive immune responses.Our previous work suggested that chronic psychological stress might lead to the expansion of both CD11b+Gr1hi and CD11b+Gr1int MDSC subpopulations in the bone marrow, as well as their mobilization to the peripheral blood and accumulation in the spleens. Cyclic AMP (cAMP) is the first identified intracellular mediator (second messenger) of stress hormone action.Based on our long-term studies in cAMP field and the resources of our facility, we prepare to investigate the effects of chronic psychological stress on the absolute numbers, percentages, phenotypes, and fuctions of MDSC and the underlying mechanisms. The corresponding findings might achieve therorical breakthroughs about the pathogenic mechanisms of chronic psychological stress and provide clues to develop intervention strategies and drugs.

我国正处于快速发展的转型期，社会心理问题日益突出。已证实长期的精神压力和情绪低落会使机体抗感染能力下降，而自身免疫病复发和恶性肿瘤发生/转移的可能性增加。尽管人们对慢性心理应激干扰免疫效应细胞的分子机制已经有所了解，但慢性心理应激对免疫调节细胞亚群的影响还是未知的。髓系来源抑制细胞（myeloid-derived suppressor cells, MDSC）是具有重要免疫调节作用的细胞亚群。我们的前期工作提示，慢性心理应激扩增和动员MDSC。慢性心理应激导致体内应激激素如儿茶酚胺水平持续升高，而儿茶酚胺发挥效应依赖于细胞内的第二信使cAMP，基于我们在cAMP领域的长期研究和依托单位在心理、认知方面的完善的技术平台和资源优势，我们准备探讨慢性心理应激对MDSC数量、表型、功能的影响和机制。本项目的完成可望为慢性心理应激病理机制的研究取得理论上的突破，并为相应的干预治疗提供线索。

我国正处于快速发展的转型期，社会心理问题日益突出。已证实长期的精神压力和情绪低落会使机体抗感染能力下降，而自身免疫病复发和恶性肿瘤发生/转移的可能性增加。尽管人们对慢性心理应激干扰免疫效应细胞的分子机制已经有所了解，但慢性心理应激对免疫调节细胞亚群的影响还是未知的。髓系来源抑制细胞（myeloid-derived suppressor cells, MDSCs）是具有重要免疫调节作用的细胞亚群。我们的工作表明，在小鼠模型中慢性心理应激扩增和动员CD11b+Gr1+ MDSCs，同时人周血CD11b+CD33+HLA-DRlow/neg MDSCs的比例与长期心理问题严重程度正相关。慢性心理应激导致体内应激激素如糖皮质激素、儿茶酚胺水平持续升高，儿茶酚胺自身不足以诱导MDSCs积聚，儿茶酚胺特异阻断剂逆转MDSCs扩增、动员，而糖皮质激素特异阻断剂无作用，说明儿茶酚胺在这个过程中发挥主导作用。进一步，我们发现COX-2-PGE2环在儿茶酚胺下游诱导MDSCs积聚，COX-2特异阻断剂SC-236逆转MDSCs的扩增、动员。积聚的MDSCs表达多种抑制分子包括iNOS, PD-L2和FasL，自身表达较高水平TNF-alpha，而抑制巨噬细胞表达炎性细胞因子并抑制T细胞增殖。我们的结果为慢性心理应激病理机制的研究取得了理论上的进展，并为相应的干预治疗提供了线索。并提示MDSCs的扩增和动员可作为慢性心理应激诊断的指征。