Abstract
Emerging evidence implied that chronic stress has been exerting detrimental impact on immune system functions in both humans and animals. Toll-like receptors (TLRs) have been shown to play an essential role in modulating immune responses and cell survival. We have recently shown that TLR9 deficiency protects against lymphocyte apoptosis induced by chronic stress. However, the exact role of TLR9 in stress-mediated change of macrophage function remains unclear. The results of the current study showed that when BALB/c mice were treated with restraint stress (12 h daily for 2 days), the number of macrophages recruited to the peritoneal cavity was obviously increased. Results also demonstrated that the sustained effects of stress elevated cytokine IL-1β, TNF-α and IL-10 production yet diminished IFN-γ production from macrophage, which led to apoptotic cell death. However, TLR9 deficiency prevented the chronic stress-mediated accumulation of macrophages. In addition, knocking out TLR9 significantly abolished the chronic stress-induced imbalance of cytokine levels and apoptosis in macrophage. TLR9 deficiency was also found to reverse elevation of plasma IL-1β, IL-10 and IL-17 levels and decrease of plasma IFN-γ level under the condition of chronic stress. These results indicated that TLR9-mediated macrophage responses were required for chronic stress-induced immunosuppression. Further exploration showed that TLR9 deficiency prevented the increment of p38 MAPK phosphorylation and reduction of Akt/Gsk-3β phosphorylation; TLR9 deficiency also attenuated the release of mitochondrial cytochrome c into cytoplasm, caused upregulation of Bcl-2/Bax protein ratio, downregulation of cleavage of caspase-3 and PARP, as well as decreased TUNEL-positive cells in macrophage of stressed mice. Collectively, our studies demonstrated that deficiency of TLR9 maintained macrophage function by modulating macrophage accumulation and attenuating macrophage apoptosis, thus preventing immunosuppression in restraint-stressed mice.
Highlights
Experimental studies and clinical observations have indicated that stress serves as an important risk factor in the etiology of infectious and autoimmune diseases [1, 2]
We demonstrated that tumor necrosis factor (TNF)-α, IL-1βand IL-10 production, as well as p38 activation, cleaved caspase-3 and cleaved poly ADP-ribose polymerase (PARP) induced by chronic stress were impaired in macrophages from TLR9-deficient mice
Several lines of evidence suggest that TLR9 seems to participate in chronic stress-mediated immune suppression, the involvement of TLR9 in functional change of macrophages following chronic stress treatment has not yet been addressed
Summary
Experimental studies and clinical observations have indicated that stress serves as an important risk factor in the etiology of infectious and autoimmune diseases [1, 2] Both acute and chronic stress has been found to have dramatic impacts on the immunological parameters in both humans and animals. As one of the most important immune cells, macrophages might express inducible nitric oxide synthase (iNOS), H2O2, tumor necrosis factor (TNF)-α and interleukin (IL)-1, which participate in the macrophage-induced suppression of immune responses[6] [7]. It remains unknown whether macrophages are involved with the immune suppression due to chronic stress. We employed the physical restraint stress mouse model to examine the relationship between chronic stress and macrophage, and to explore the effect of chronic stress on macrophage apoptosis and the possible molecular mechanism
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