Toll样受体在先天免疫和细胞损伤中的作用
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摘要
Toll-like receptor 2 (TLR2), a key immune receptor in the TLR family, is widely expressed in various systems, including the immune and nervous systems and plays a critical role in controlling innate and adaptive immune responses. We previously reported that opioids inhibit cell growth and trigger apoptosis. However, the underlying mechanism by which TLR2 mediates apoptosis in response to opioids is not yet known. Here we show that chronic morphine treatment in primary neurons dramatically increased the expression of TLR2 at both the messenger RNA and protein levels. In addition, TLR2 deficiency significantly inhibited chronic morphine-induced apoptosis in primary neurons. Activation of caspase-3 after morphine treatment is impaired in TLR2 deficient primary neurons. Moreover, morphine treatment failed to induce an increased level of phosphorylated glycogen synthase kinase 3 beta (GSK3β) in TLR2 deficient primary neurons, suggesting an involvement of GSK3βin morphine-mediated TLR2 signaling. These results thus demonstrate that opioids prime neurons to undergo apoptosis by inducing TLR2 expression. Our data suggest that inhibition of TLR2 is capable of preventing opioids-induced damage to neurons.
Opioids are powerful pain relievers, but also potent inducers of dependence and tolerance. Chronic morphine administration (via subcutaneous pellet) induces morphine dependence in the nucleus accumbens, a key dependence region in the brain, yet the cellular mechanisms are mostly unknown. Toll-like receptor 2 (TLR2) plays an essential function in controlling innate and inflammatory responses. Using a knockout mouse lacking TLR2, we assessed the contribution of TLR2 to the development of morphine dependence and microglia activation. We report here that mice deficient in TLR2 inhibit morphine-induced the levels of microglia activation and proinflammatory cytokines. Moreover, in TLR2 knockout mice the main symptoms of morphine withdrawal were significantly attenuated. Our data demonstrate that TLR2 is critical for opioid dependence and is a factor in response to innate immune response.
As resveratrol derivatives, resveratrol aliphatic acids were synthesized in our laboratory. Previously, we reported the improved pharmaceutical properties of the compounds compared to resveratrol, including better solubility in water and much tighter binding with human serum albumin. Here, we investigate the role of resveratrol aliphatic acids in Toll-like receptor 2 (TLR2)-mediated apoptosis. We showed that resveratrol aliphatic acid (R6A) significantly inhibits the expression of TLR2. In addition, overexpression of TLR2 in HEK293 cells caused a significant decrease in apoptosis after R6A treatment. Moreover, inhibition of TLR2 by R6A decreases serum deprivation-reduced the levels of phosphorylated Akt and phosphorylated glycogen synthase kinase 3(3 (GSK3β). Our study thus demonstrates that the resveratrol aliphatic acid inhibits cell apoptosis through TLR2 by the involvement of Akt/GSK3βpathway.
TLR4 (Toll-like receptor-4), a key member of the TLRs family, has been well characterized by its function in induction of inflammatory products of innate immunity. However, the involvement of TLR4 in a variety of apoptotic events with an unknown mechanism recently interests great research focus. Our investigation found that TLR4 promoted apoptotic signaling through affecting glycogen synthase kinase-3β(GSK-3(3) pathway in the serum deprivation (SD)-induced apoptotic paradigm. SD induces GSK-3βactivation in a pathway that leads to subsequent cell apoptosis. Intriguingly, this apoptotic cascade is amplified in presence of TLR4 whereas greatly attenuated byβ-arrestin 2, another critical molecule implicated in TLR4 mediated immune responses. Our data suggest the association ofβ-arrestin 2 with GSK-3βcontributes to the stabilization of phospho-GSK-3(3, an inactive form of GSK-3p. It becomes a critical determinant for the attenuation of TLR4-initiated apoptosis byβ-arrestin 2. Taken together, we demonstrate that the TLR4 possesses the capability of accelerating GSK-3βactivation thereby deteriorating SD-induced apoptosis;β-arrestin 2 represents an inhibitory effect on TLR4-mediated apoptotic cascade, through controlling the homeostasis of activation and inactivation of GSK-3p.
Stress, either physical or psychological, can modulate immune function. However, the mechanisms associated with stress-induced immune suppression remains to be elucidated. P-arrestin 2 serves as adaptors, scaffolds, and/or signal transducers. The role ofβ-arrestin 2 in stress-induced immune suppression is not known yet. Here, we demonstrate thatβ-arrestin 2 deficiency in mice increases the sensitivity of chronic stress-induced lymphocyte reduction. Interestingly, the stress-induced suppression of T help 1 (Th1) cytokine and increased production of Th2 cytokine was greatly increased in P-arrestin 2 deficient mice compared with wild type mice. Moreover, inhibition of PI3K in P-arrestin 2-deficient mice exerts an additive effect on stress-induced lymphocyte reduction. Our study thus demonstrates thatβ-arrestin 2 plays an important role in stress-induced immune suppression.
Background:Although it is established that opioid and Mycobacterium tuberculosis are both public health problems, the mechanisms by which they affect lung functions remain elusive. Methodology/Principal Findings:We report here that mice subjected to chronic morphine administration and M. tuberculosis infection exhibited significant apoptosis in the lung in wild type mice as demonstrated by the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling assay. Morphine and M. tuberculosis significantly induced the expression of Toll-like receptor 9 (TLR9), a key mediator of innate immunity and inflammation. Interestingly, deficiency in TLR9 significantly inhibited the morphine and M. tuberculosis induced apoptosis in the lung. In addition, chronic morphine treatment and M. tuberculosis infection enhanced the levels of cytokines (TNF-a, IL-1β, and IL-6) in wild type mice, but not in TLR9 knockout (KO) mice. The bacterial load was much lower in TLR9 KO mice compared with that in wild type mice following morphine and M. tuberculosis treatment. Morphine alone did not alter the bacterial load in either wild type or TLR9 KO mice. Moreover, administration of morphine and M. tuberculosis decreased the levels of phosphorylation of Akt and GSK3βin the wild type mice, but not in TLR9 KO mice, suggesting an involvement of Akt/GSK3p in morphine and M. tuberculosis-mediated TLR9 signaling. Furthermore, administration of morphine and M. tuberculosis caused a dramatic decrease in Bcl-2 level but increase in Bax level in wild type mice, but not in TLR9 KO mice, indicating a role of Bcl-2 family in TLR9-mediated apoptosis in the lung following morphine and M. tuberculosis administration. Conclusions/Significance:These data reveal a role for TLR9 in the immune response to opioids during M. tuberculosis infection.
Opioids have been widely applied in clinics as one of the most potent pain relievers for centuries, but their abuse has deleterious physiological effects beyond addiction. We previously reported that opioids inhibit cell growth and trigger apoptosis in lymphocytes. However, the underlying mechanism by which microglia apoptosis in response to opioids is not yet known. In this study, we show that morphine induces microglia apoptosis and caspase-3 activation in an opioid-receptor dependent manner. Morphine decreased the levels of microglia phosphorylated Akt (p-Akt) and p-GSK-3β(glycogen synthase kinase 3 beta) in an opioid receptor dependent manner. More interestingly, GSK-3βinhibitor SB216763 significantly increased morphine-induced apoptosis in both BV-2 microglia and mouse primary microglial cells. Moreover, co-treatment of microglia with SB216763 and morphine led to a significant synergistic effect on the level of phospho-p38 mitogen-activated protein kinase (MAPK). In addition, inhibition of p38 MAPK by its specific inhibitor SB203580 significantly inhibited morphine-induced apoptosis and caspase-3 activation. Taken together, our data clearly demonstrates that morphine induces apoptosis in microglial cells, which is mediated via GSK-3βand p38 MAPK pathways.
引文
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