Abstract
BackgroundPsychological 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.ResultsWe 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.ConclusionChronic 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.
Highlights
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
Spleens from stressed mice exhibited higher autophagy level by IHC than those from control mice (Fig. 1b). These results suggest that chronic stress induces autophagy in mouse spleens
We propose that chronic stress-induced high level of galectin-9 binds to T cell immunoglobulin and mucin domain 3 (Tim-3) to regulate autophagy and immune system function and this combination could represent a novel and potential therapeutic approach in chronic stress induced immunosuppression
Summary
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. Autophagy plays an essential role in modulating cellular homeostasis and immune responses It is not known yet whether autophagy contributes to chronic stress-induced immunosuppression. Misregulation of autophagy can result in susceptibility to autoimmune and inflammatory diseases including chronic inflammatory bowel disease, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus (SLE), infectious diseases and cancers [14, 16]. With these diverse and extensive immunerelated functions for autophagy, it is essential to further explore the role of autophagy in the modulations of immune suppression following chronic stress
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