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The role of toll-like receptor 9 in chronic stress-induced apoptosis in macrophage.

Xiang Y, Yan H, Zhou J, Zhang Q, Hanley G, Caudle Y, LeSage G, Zhang X, Yin D - PLoS ONE (2015)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine, College of Medicine, East Tennessee State University, Johnson City, Tennessee 37614, United States of America; Department of Pharmacology, Shandong University School of Medicine, Jinan, People's Republic of China.

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.

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A deficiency of TLR9 suppressed change of cytokine levels caused by chronic stress.TLR9 knockout mice or wild type BALB/c mice aged 6 to 8 weeks were subjected to a 12 h physical restraint daily. After 2 d stress, mice were sacrificed by cervical dislocation, and the serum were harvested and the levels of IL-1β, IL-10, IL-17 and IFN-γ in serum were examined by ELISA kit. Means and SEs were calculated from 7 mice per group. *p < 0.05, **p< 0.01 compared with indicated groups.
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pone.0123447.g003: A deficiency of TLR9 suppressed change of cytokine levels caused by chronic stress.TLR9 knockout mice or wild type BALB/c mice aged 6 to 8 weeks were subjected to a 12 h physical restraint daily. After 2 d stress, mice were sacrificed by cervical dislocation, and the serum were harvested and the levels of IL-1β, IL-10, IL-17 and IFN-γ in serum were examined by ELISA kit. Means and SEs were calculated from 7 mice per group. *p < 0.05, **p< 0.01 compared with indicated groups.

Mentions: It is known that excessive production of plasma proinflammatory cytokines in response to chronic stress can promote the development of immune suppression. We next assessed the expression of IL-1β, IL-10, IL-17 and IFN-γ in the serum of wild type and TLR9 knockout mice challenged with chronic stress. Our data showed that expression level of IL-1β, IL-10, IL-17 in the serum of stressed wild type mice increased by 3.3-, 2.9- and 2.8-fold, compared to that of control wild type mice, respectively. However, the expression level of IL-1β, IL-10, IL-17 did not differ between the control TLR9 knockout mice and stressed TLR9 knockout mice (Fig 3A, 3B and 3C). Chronic stress significantly inhibited IFN-γ production in the serum from stressed wild type mice by 2.1-fold than serum from control wild type mice, but chronic stress failed to induce the change in TLR9 kncokout mice (Fig 3D).


The role of toll-like receptor 9 in chronic stress-induced apoptosis in macrophage.

Xiang Y, Yan H, Zhou J, Zhang Q, Hanley G, Caudle Y, LeSage G, Zhang X, Yin D - PLoS ONE (2015)

A deficiency of TLR9 suppressed change of cytokine levels caused by chronic stress.TLR9 knockout mice or wild type BALB/c mice aged 6 to 8 weeks were subjected to a 12 h physical restraint daily. After 2 d stress, mice were sacrificed by cervical dislocation, and the serum were harvested and the levels of IL-1β, IL-10, IL-17 and IFN-γ in serum were examined by ELISA kit. Means and SEs were calculated from 7 mice per group. *p < 0.05, **p< 0.01 compared with indicated groups.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4401452&req=5

pone.0123447.g003: A deficiency of TLR9 suppressed change of cytokine levels caused by chronic stress.TLR9 knockout mice or wild type BALB/c mice aged 6 to 8 weeks were subjected to a 12 h physical restraint daily. After 2 d stress, mice were sacrificed by cervical dislocation, and the serum were harvested and the levels of IL-1β, IL-10, IL-17 and IFN-γ in serum were examined by ELISA kit. Means and SEs were calculated from 7 mice per group. *p < 0.05, **p< 0.01 compared with indicated groups.
Mentions: It is known that excessive production of plasma proinflammatory cytokines in response to chronic stress can promote the development of immune suppression. We next assessed the expression of IL-1β, IL-10, IL-17 and IFN-γ in the serum of wild type and TLR9 knockout mice challenged with chronic stress. Our data showed that expression level of IL-1β, IL-10, IL-17 in the serum of stressed wild type mice increased by 3.3-, 2.9- and 2.8-fold, compared to that of control wild type mice, respectively. However, the expression level of IL-1β, IL-10, IL-17 did not differ between the control TLR9 knockout mice and stressed TLR9 knockout mice (Fig 3A, 3B and 3C). Chronic stress significantly inhibited IFN-γ production in the serum from stressed wild type mice by 2.1-fold than serum from control wild type mice, but chronic stress failed to induce the change in TLR9 kncokout mice (Fig 3D).

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine, College of Medicine, East Tennessee State University, Johnson City, Tennessee 37614, United States of America; Department of Pharmacology, Shandong University School of Medicine, Jinan, People's Republic of China.

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.

Show MeSH
Related in: MedlinePlus