Qin Anna, Zhong Ting, Zou Huajiao, Wan Xiaoya, Yao Bifeng, Zheng Xinbin, Yin Deling
1Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410008 Hunan China.
2Department of Internal Medicine, College of Medicine, East Tennessee State University, Johnson City, TN 37614 USA.
Cell Biosci. 2019 Jan 22;9:13. doi: 10.1186/s13578-019-0275-1. eCollection 2019.
Psychological and physical stress can either enhance or suppress immune functions depending on a variety of factors such as duration and severity of stressful situation. Chronic stress exerts a significantly suppressive effect on immune functions. However, the mechanisms responsible for this phenomenon remain to be elucidated. Autophagy plays an essential role in modulating cellular homeostasis and immune responses. However, it is not known yet whether autophagy contributes to chronic stress-induced immunosuppression. T cell immunoglobulin and mucin domain 3 (Tim-3) has shown immune-suppressive effects and obviously positive regulation on cell apoptosis. Tim-3 combines with Tim-3 ligand galectin-9 to modulate apoptosis. However, its impact on autophagy and chronic stress-induced immunosuppression is not yet identified.
We found remarkably higher autophagy level in the spleens of mice that were subjected to chronic restraint stress compared with the control group. We also found that inhibition of autophagy by the autophagy inhibitor 3-methyladenine (3-MA) significantly attenuated chronic stress-induced alterations of pro-inflammatory and anti-inflammatory cytokine levels. We further elucidated that 3-MA dramatically inhibited the reduction of lymphocyte numbers. Moreover, chronic stress dramatically enhanced the expression of Tim-3 and galectin-9. Inhibition of Tim-3 by small interfering RNA against Tim-3 significantly decreased the level of autophagy and immune suppression in isolated primary splenocytes from stressed mice. In addition, α-lactose, a blocker for the interaction of Tim-3 and galectin-9, also decreased the autophagy level and immune suppression.
Chronic stress induces autophagy, resulting with suppression of immune system. Tim-3 and galectin-9 play a crucial regulatory role in chronic stress-induced autophagy. These studies suggest that Tim-3 mediated autophagy may offer a novel therapeutic strategy against the deleterious effects of chronic stress on the immune system.
心理和生理应激可增强或抑制免疫功能，这取决于多种因素，如应激情况的持续时间和严重程度。慢性应激对免疫功能有显著的抑制作用。然而，导致这种现象的机制仍有待阐明。自噬在调节细胞内稳态和免疫反应中起着至关重要的作用。然而，目前尚不清楚自噬是否参与慢性应激诱导的免疫抑制。T细胞免疫球蛋白和粘蛋白结构域3（Tim-3）已显示出免疫抑制作用，并对细胞凋亡有明显的正向调节作用。Tim-3与Tim-3配体半乳糖凝集素-9结合以调节细胞凋亡。然而，其对自噬和慢性应激诱导的免疫抑制的影响尚未明确。
我们发现，与对照组相比，遭受慢性束缚应激的小鼠脾脏中的自噬水平显著更高。我们还发现，自噬抑制剂3-甲基腺嘌呤（3-MA）抑制自噬可显著减轻慢性应激诱导的促炎和抗炎细胞因子水平的改变。我们进一步阐明，3-MA显著抑制淋巴细胞数量的减少。此外，慢性应激显著增强了Tim-3和半乳糖凝集素-9的表达。针对Tim-3的小干扰RNA抑制Tim-3可显著降低应激小鼠分离的原代脾细胞中的自噬水平和免疫抑制。此外，α-乳糖，一种Tim-3与半乳糖凝集素-9相互作用的阻断剂，也降低了自噬水平和免疫抑制。
慢性应激诱导自噬，导致免疫系统受到抑制。Tim-3和半乳糖凝集素-9在慢性应激诱导的自噬中起关键调节作用。这些研究表明，Tim-3介导的自噬可能为对抗慢性应激对免疫系统的有害影响提供一种新的治疗策略。
