阿片类药物对肺炎链球菌感染模型固有免疫的调节及机制研究
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摘要
大量研究表明,阿片类药物滥用通过破坏免疫系统固有免疫和适应性免疫进而引起免疫抑制。然而,阿片类药物滥用增加肺炎链球菌肺部易感性的确切机制目前还不明了。白细胞介素- 23(IL-23)是由激活的巨噬细胞和树突状细胞(DCs)分泌,并诱导记忆性T细胞增殖,是机体响应细菌的挑战时T细胞表达白细胞介素- 17(IL-17)的关键因素。IL-23/IL-17轴在肺炎链球菌肺部感染过程是否有助于调节固有免疫还没有得到明确阐述。阿片类药物吗啡调节肺炎链球菌引起IL- 23产生的细胞和分子机制也有待澄清。
本研究使用已建立的阿片类药物滥用和肺炎链球菌肺部感染的小鼠模型与细胞感染模型,采用ELISA、Real time PCR、Western blot、流式细胞术、免疫荧光技术、瞬时转染等免疫学与分子生物学技术,在整体、细胞与分子水平研究了阿片类药物吗啡对肺炎链球菌感染模型固有免疫的调节及机制。
采用阿片类药物滥用和肺炎链球菌肺部感染的鼠体内模型,发现了吗啡能削弱IL-23/IL-17早期产生与中性粒细胞迁移延迟和细菌清除减少有关;给予鼠重组IL-17蛋白明显的改善了宿主肺部的抗菌能力并降低了细菌散播到血液中;使用TCRδ-/-鼠实验显示IL- 17水平降低,机体清除感染的能力下降;肺炎链球菌感染早期,吗啡可抑制抗菌蛋白质S100A9和S100A8/A9的分泌。这些结果表明吗啡能引起产生IL-23的DCs和产生IL-17的γδT淋巴细胞的功能紊乱,并导致S100A9和S100A8/A9分泌减少,中性粒细胞募集受损以致引起更严重感染。
用肺炎链球菌体外细胞感染模型,我们发现用肺炎链球菌、脂磷壁酸和肺炎链球菌溶血素刺激后的骨髓来源的树突状细胞(BMDCs)和巨噬细胞(BMDMs)IL-23蛋白水平显著增加。在BMDCs,吗啡能显著抑制感染诱导的IL-23启动子活性、mRNA和蛋白质水平;脂磷壁酸和胞壁酰二肽联合诱导产生的IL–23与感染诱导的水平相同;用MyD88和IRAK1/4抑制剂,或TLR2抗体预处理后,感染诱导的IL- 23水平明显减少,并且吗啡的抑制作用消除;吗啡能抑制感染诱导的IRF-3、ATF-2和NF-κBp65的磷酸化。这些结果表明吗啡能够削弱肺炎链球菌诱导DCs产生IL-23,这种削弱是通过MyD88-IRAK1/4依赖性的TLR2和Nod2协同的信号传导通路来实现的。
本研究为发展治疗、干预和控制药物滥用人群肺炎链球菌感染提供了重要理论基础和新颖的方法依据,具有重要的生物学意义和潜在临床应用价值。此项目的长期目标是深入了解调节肺部天然免疫的确切分子机制,以便发展新的有效的辅助疗法来完善标准的治疗方法,提高阿片类药物滥用者的机体免疫功能和肺部抗感染能力。
Streptococcus pneumoniae is a pathogen that causes serious respiratory disease and meningitis in the immunocompromised drug abuse population. However, the precise mechanisms by which drug abuse compromises the host immune defense to pulmonary S. pneumoniae infection is not fully understood. Interleukin-23 (IL-23) has been recently identified as a cytokine closely related to IL-12. IL-23 is secreted by activated macrophages and dendritic cells (DCs) and induces memory T-cell proliferation and is the critical factor required for T-cell IL-17expression in response to bacterial challenge. IL-23 release leads to the production of IL-17. Furthermore, IL-17 promotes neutrophilic inflammation by upregulating CXC chemokines and hematopoietic growth factors. However, whether the IL-23/IL-17 axis contributes to modulating the innate immunity in response to S. pneumoniae lung infection in opiate abuser has not been addressed. Resident lung phagocytic cells, primarily dendritic cells and alveolar macrophages, are likely the first immune cells exposed to S. pneumoniae upon inhalation of the organism into the lungs. Dendritic cells and alveolar macrophages express Toll-like receptors (TLRs) and nucleotide-binding oligomerization domain (Nod) receptors. However, how morphine modulates S. pneumoniae induced IL-23 production through TLRs and Nod receptors dependent signaling pathways remain to be elucidated.
In this study, we used our laboratory’s well-established murine model of opiate abuse and S. pneumoniae lung infection and in vitro cell S. pneumoniae infection model, we explored the influence of morphine treatment on the interleukin-23 (IL-23)/IL-17 axis in vivo study and how morphine treatment modulates S. pneumoniae infection induced IL-23 production in vitro study.
Chapter1: Morphine impairs innate immune functions related the IL-23/IL-17 axis following S. pneumoniae lung infection
(1)IL-23 and IL-17 expression during S. pneumoniae lung infection
IL-23/ IL-17 protein and mRNA levels following S. pneumoniae infection in the lung tissues, BAL fluids and cells were quantified. IL-23 was rapidly released as early as 2 h following S. pneumoniae infection in both the lung tissues and BAL fluids. In the lung tissues, IL-17 was detected within 2 h after S. pneumonia infection. In the BAL fluids, IL-17 was not detectable during the early stages of infection. Furthermore, mRNA levels of IL-23 and IL-17 in the lung tissues were markedly up-regulated by S. pneumoniae infection as early as 2 h.mRNA levels of IL-23 and IL-17 in the BAL cells are similar with protein levels, separately.
(2)Morphine treatment disrupts pulmonary IL-23 and IL-17 expression in the early stages of S. pneumoniae lung infection
Morphine treatment caused a decrease in both IL-23 and IL-17 synthesis during the early stages of infection. This decrease in IL-23 and IL-17 production was associated with delayed and decreased neutrophil recruitment into BAL and lung tissues following S.pneumoniae infection, and an increased bacterial burden within the lungs, and the initiation of systemic disease.
(3)Effect of rIL-17 on clearance of S. pneumoniae infection .Administration of recombinant murine IL-17 (15ng/mouse) significantly improved lung antibacterial host defense and reduced bacterial dissemination to the blood.
(4)Morphine treatment impairs AMs and DCs IL-23 production in response to in vitro cell infection
S.pneumoniae infection stimulated IL-23 production by DCs were markedly higher than that by macrophages. Morphine treatment inhibited this response in BMDC.The morphine action on S. pneumoniae induced IL-23 was abolished by naltrexone.
(5)Morphine inhibits S. pneumoniae-induced IL-23 production through the MyD88-dependent IRF-3, ATF-2, and NF-κB signaling
MyD88 inhibitor treatment resulted in decreased IL-23 production in a dose dependent manner in BMDCs.Morphine treatment caused a significant decreased in S. pneumoniae induced IL-23 production in BMDCs when pretreated with MyD88 control peptide. However, no difference in IL-23 production was observed between morphine and vehicle treated BMDCs when pretreated with MyD88 inhibitory peptide .Morphine inhibited S.pneumoniae induced IRF-3, ATF-2 and NF-κBp65 phosphorylation.
(6)γδT cells contribute to IL-17 expression in response to S. pneumoniae lung infection
S.pneumoniae infection induced IL-23 production in the BAL fluids and lung tissues of both WT and TCRδ-/- mice. Morphine treatment diminished IL-23 production in the early stages of S. pneumoniae infection. However, significant levels of IL-17 production, induced by S. pneumoniae infection, were only detected in the lungs derived from WT mice, but not in the lungs of TCRδ-/- mice. Morphine significantly impaired IL-17 production in S. pneumoniae infected WT mice. The number of live bacteria in the lungs was significantly higher (**p<0.01) in TCRδ-/- mice than in WT mice 24 h postinfection. Morphine treatment in the WT mice resulted in a greater bacterial burden in the BAL and lungs compared to placebo treated WT mice. Interestingly, no difference in bacterial burden was observed between morphine and placebo treatment of TCRδ-/- mice.
(7) Morphine inhibits the secretion of antimicrobial proteins S100A9 and S100A8/A9
Morphine treatment markedly decreased S100A9 and S100A8/A9 production in the early stages of S. pneumoniae infection.
Chapter2: Morphine modulates dendritic cell interleukin 23 production through TR2 and Nod-2 synergistic signaling
(1)Dendritic cells are main source of IL-23 in response to S. pneumoniae infection
The levels of IL-23 in the culture supernatants of BMDCs and BMDMs were significantly increased following infection with S. pneumoniae or stimulation with LTA or PLY. CpG or MDP didn’t induce a significant IL-23 production in DCs. The levels of IL-23 were about 6-fold higher in culture supernatants of BMDCs compared to those of BMDMs.
(2)Morphine modulates the promoter activity, mRNA transcription and protein production of IL-23 induced by S. pneumoniae in DCs through theμ-opioid receptors
Morphine treatment resulted in an approximately 65 % reduction in IL-23 promoter activity and mRNA levels and more than 50% of IL-23 production when compared with vehicle control in DCs derived from WT mice. Moreover, this morphine effect on IL-23 protein production was completely abolished in DCs derived from MORKO mice.
(3)Morphine impairs IL-23 production following S. pneumoniae infection through the TLR2 in synergy with Nod2 signaling pathway
DCs were stimulated with single TLR or Nod2 agonist, or combination of TLRs and Nod2 agonists. The combination of MDP and LTA stimulated a significant IL-23 `production, which was at same level of IL-23 production as S. pneumoniae infection. Morphine treatment significantly inhibited these effects.
Pretreatment of DCs with anti-TLR2 partially attenuated S. pneumoniae induced IL-23 production. Furthermore, pretreatment of DCs with anti-TLR2 abolished inhibitory effect of morphine on IL-23 production following the infection.
(4)Effect of S. pneumoniae infection and morphine treatment on the expressions of TLRs
FACS shows that S. pneumoniae infection induced the TLR2 and 4 expressions in DCs. However, morphine treatment did not significantly alter the expressions of TLRs in DCs.
(5)Morphine treatment impairs IL-23 production in a MyD88-IRAK1/4 dependent manner
MyD88 inhibitory peptide significantly inhibited S. pneumoniae induced IL-23 production in a dose dependent manner, Meanwhile MyD88 control peptide did not show a significant effect on IL-23 production. When DCs were pretreated with MyD88 control peptide, morphine treatment resulted in a decrease in S. pneumoniae, LTA and PLY induced IL-23 production. However, when DCs were pretreated with MyD88 inhibitor, no difference in IL-23 production was observed between morphine and vehicle treated DCs following infection with S. pneumoniae or stimulated with LTA or PLY.
The IRAK1/4 inhibitor caused a clear reduction in IL-23 production following the infection. Pretreatment of DCs with IRAK1/4 inhibitor totally attenuated the inhibitory actions of morphine on IL-23 production following S. pneumoniae
(6)Morphine treatment modulates the phosphoralytion of ATF-2 and IRF-3 induced by infection with S. pneumoniae or stimulated with TLR2 plus Nod2 ligands
DCs were infected with S. pneumoniae or stimulated with LTA, MDP or LTA plus MDP for 45 min, then fixed and stained for the subcellular distribution of IRF-3 and ATF-2 using immune-fluorescence staining. We only detected a nuclear translocation of IRF3 and ATF2 in response to infection with S. pneumoniae, and stimulation with LTA plus MDP, or LTA alone. Morphine treatment significantly decreased the phosphorylation of IRF-3 and ATF-2.
(7)Cyclic AMP is involved in the inhibitory effects of morphine on S. pneumoniae induced IL-23 production
When compared with non-infected DCs, S. pneumoniae infection didn’t cause an alteration in levels of intracellular cAMP determined by immunoassay. Chronic morphine treatment resulted in a significant increase in intracellular cAMP in DCs. Forskolin treatment significantly inhibited IL-23 production in S. pneumoniae infected DCs, and abolished morphine’s inhibitory effect.
Conclusion
Morphine treatment causes a dysfunction in IL-23-producing dendritic cells and macrophages and IL-17-producingγδT lymphocytes in response to S. pneumoniae lung infection. This leads to diminished release of antimicrobial S100A8/A9 proteins, compromised neutrophil recruitment, and more-severe infection. Morphine impairs S. pneumoniae induced IL-23 production through MyD88-IRAK1/4-IRF3 and MyD88-IRAK1/4- ATF2 dependent TLR2 and Nod-2 synergistic signaling in DCs. Morphine-induced increase intracellular cAMP throughμ-opioid receptor may be a potential mechanism by which morphine treatment inhibits S. pneumonia infection induced IL-23 production.
本研究使用已建立的阿片类药物滥用和肺炎链球菌肺部感染的小鼠模型与细胞感染模型,采用ELISA、Real time PCR、Western blot、流式细胞术、免疫荧光技术、瞬时转染等免疫学与分子生物学技术,在整体、细胞与分子水平研究了阿片类药物吗啡对肺炎链球菌感染模型固有免疫的调节及机制。
采用阿片类药物滥用和肺炎链球菌肺部感染的鼠体内模型,发现了吗啡能削弱IL-23/IL-17早期产生与中性粒细胞迁移延迟和细菌清除减少有关;给予鼠重组IL-17蛋白明显的改善了宿主肺部的抗菌能力并降低了细菌散播到血液中;使用TCRδ-/-鼠实验显示IL- 17水平降低,机体清除感染的能力下降;肺炎链球菌感染早期,吗啡可抑制抗菌蛋白质S100A9和S100A8/A9的分泌。这些结果表明吗啡能引起产生IL-23的DCs和产生IL-17的γδT淋巴细胞的功能紊乱,并导致S100A9和S100A8/A9分泌减少,中性粒细胞募集受损以致引起更严重感染。
用肺炎链球菌体外细胞感染模型,我们发现用肺炎链球菌、脂磷壁酸和肺炎链球菌溶血素刺激后的骨髓来源的树突状细胞(BMDCs)和巨噬细胞(BMDMs)IL-23蛋白水平显著增加。在BMDCs,吗啡能显著抑制感染诱导的IL-23启动子活性、mRNA和蛋白质水平;脂磷壁酸和胞壁酰二肽联合诱导产生的IL–23与感染诱导的水平相同;用MyD88和IRAK1/4抑制剂,或TLR2抗体预处理后,感染诱导的IL- 23水平明显减少,并且吗啡的抑制作用消除;吗啡能抑制感染诱导的IRF-3、ATF-2和NF-κBp65的磷酸化。这些结果表明吗啡能够削弱肺炎链球菌诱导DCs产生IL-23,这种削弱是通过MyD88-IRAK1/4依赖性的TLR2和Nod2协同的信号传导通路来实现的。
本研究为发展治疗、干预和控制药物滥用人群肺炎链球菌感染提供了重要理论基础和新颖的方法依据,具有重要的生物学意义和潜在临床应用价值。此项目的长期目标是深入了解调节肺部天然免疫的确切分子机制,以便发展新的有效的辅助疗法来完善标准的治疗方法,提高阿片类药物滥用者的机体免疫功能和肺部抗感染能力。
Streptococcus pneumoniae is a pathogen that causes serious respiratory disease and meningitis in the immunocompromised drug abuse population. However, the precise mechanisms by which drug abuse compromises the host immune defense to pulmonary S. pneumoniae infection is not fully understood. Interleukin-23 (IL-23) has been recently identified as a cytokine closely related to IL-12. IL-23 is secreted by activated macrophages and dendritic cells (DCs) and induces memory T-cell proliferation and is the critical factor required for T-cell IL-17expression in response to bacterial challenge. IL-23 release leads to the production of IL-17. Furthermore, IL-17 promotes neutrophilic inflammation by upregulating CXC chemokines and hematopoietic growth factors. However, whether the IL-23/IL-17 axis contributes to modulating the innate immunity in response to S. pneumoniae lung infection in opiate abuser has not been addressed. Resident lung phagocytic cells, primarily dendritic cells and alveolar macrophages, are likely the first immune cells exposed to S. pneumoniae upon inhalation of the organism into the lungs. Dendritic cells and alveolar macrophages express Toll-like receptors (TLRs) and nucleotide-binding oligomerization domain (Nod) receptors. However, how morphine modulates S. pneumoniae induced IL-23 production through TLRs and Nod receptors dependent signaling pathways remain to be elucidated.
In this study, we used our laboratory’s well-established murine model of opiate abuse and S. pneumoniae lung infection and in vitro cell S. pneumoniae infection model, we explored the influence of morphine treatment on the interleukin-23 (IL-23)/IL-17 axis in vivo study and how morphine treatment modulates S. pneumoniae infection induced IL-23 production in vitro study.
Chapter1: Morphine impairs innate immune functions related the IL-23/IL-17 axis following S. pneumoniae lung infection
(1)IL-23 and IL-17 expression during S. pneumoniae lung infection
IL-23/ IL-17 protein and mRNA levels following S. pneumoniae infection in the lung tissues, BAL fluids and cells were quantified. IL-23 was rapidly released as early as 2 h following S. pneumoniae infection in both the lung tissues and BAL fluids. In the lung tissues, IL-17 was detected within 2 h after S. pneumonia infection. In the BAL fluids, IL-17 was not detectable during the early stages of infection. Furthermore, mRNA levels of IL-23 and IL-17 in the lung tissues were markedly up-regulated by S. pneumoniae infection as early as 2 h.mRNA levels of IL-23 and IL-17 in the BAL cells are similar with protein levels, separately.
(2)Morphine treatment disrupts pulmonary IL-23 and IL-17 expression in the early stages of S. pneumoniae lung infection
Morphine treatment caused a decrease in both IL-23 and IL-17 synthesis during the early stages of infection. This decrease in IL-23 and IL-17 production was associated with delayed and decreased neutrophil recruitment into BAL and lung tissues following S.pneumoniae infection, and an increased bacterial burden within the lungs, and the initiation of systemic disease.
(3)Effect of rIL-17 on clearance of S. pneumoniae infection .Administration of recombinant murine IL-17 (15ng/mouse) significantly improved lung antibacterial host defense and reduced bacterial dissemination to the blood.
(4)Morphine treatment impairs AMs and DCs IL-23 production in response to in vitro cell infection
S.pneumoniae infection stimulated IL-23 production by DCs were markedly higher than that by macrophages. Morphine treatment inhibited this response in BMDC.The morphine action on S. pneumoniae induced IL-23 was abolished by naltrexone.
(5)Morphine inhibits S. pneumoniae-induced IL-23 production through the MyD88-dependent IRF-3, ATF-2, and NF-κB signaling
MyD88 inhibitor treatment resulted in decreased IL-23 production in a dose dependent manner in BMDCs.Morphine treatment caused a significant decreased in S. pneumoniae induced IL-23 production in BMDCs when pretreated with MyD88 control peptide. However, no difference in IL-23 production was observed between morphine and vehicle treated BMDCs when pretreated with MyD88 inhibitory peptide .Morphine inhibited S.pneumoniae induced IRF-3, ATF-2 and NF-κBp65 phosphorylation.
(6)γδT cells contribute to IL-17 expression in response to S. pneumoniae lung infection
S.pneumoniae infection induced IL-23 production in the BAL fluids and lung tissues of both WT and TCRδ-/- mice. Morphine treatment diminished IL-23 production in the early stages of S. pneumoniae infection. However, significant levels of IL-17 production, induced by S. pneumoniae infection, were only detected in the lungs derived from WT mice, but not in the lungs of TCRδ-/- mice. Morphine significantly impaired IL-17 production in S. pneumoniae infected WT mice. The number of live bacteria in the lungs was significantly higher (**p<0.01) in TCRδ-/- mice than in WT mice 24 h postinfection. Morphine treatment in the WT mice resulted in a greater bacterial burden in the BAL and lungs compared to placebo treated WT mice. Interestingly, no difference in bacterial burden was observed between morphine and placebo treatment of TCRδ-/- mice.
(7) Morphine inhibits the secretion of antimicrobial proteins S100A9 and S100A8/A9
Morphine treatment markedly decreased S100A9 and S100A8/A9 production in the early stages of S. pneumoniae infection.
Chapter2: Morphine modulates dendritic cell interleukin 23 production through TR2 and Nod-2 synergistic signaling
(1)Dendritic cells are main source of IL-23 in response to S. pneumoniae infection
The levels of IL-23 in the culture supernatants of BMDCs and BMDMs were significantly increased following infection with S. pneumoniae or stimulation with LTA or PLY. CpG or MDP didn’t induce a significant IL-23 production in DCs. The levels of IL-23 were about 6-fold higher in culture supernatants of BMDCs compared to those of BMDMs.
(2)Morphine modulates the promoter activity, mRNA transcription and protein production of IL-23 induced by S. pneumoniae in DCs through theμ-opioid receptors
Morphine treatment resulted in an approximately 65 % reduction in IL-23 promoter activity and mRNA levels and more than 50% of IL-23 production when compared with vehicle control in DCs derived from WT mice. Moreover, this morphine effect on IL-23 protein production was completely abolished in DCs derived from MORKO mice.
(3)Morphine impairs IL-23 production following S. pneumoniae infection through the TLR2 in synergy with Nod2 signaling pathway
DCs were stimulated with single TLR or Nod2 agonist, or combination of TLRs and Nod2 agonists. The combination of MDP and LTA stimulated a significant IL-23 `production, which was at same level of IL-23 production as S. pneumoniae infection. Morphine treatment significantly inhibited these effects.
Pretreatment of DCs with anti-TLR2 partially attenuated S. pneumoniae induced IL-23 production. Furthermore, pretreatment of DCs with anti-TLR2 abolished inhibitory effect of morphine on IL-23 production following the infection.
(4)Effect of S. pneumoniae infection and morphine treatment on the expressions of TLRs
FACS shows that S. pneumoniae infection induced the TLR2 and 4 expressions in DCs. However, morphine treatment did not significantly alter the expressions of TLRs in DCs.
(5)Morphine treatment impairs IL-23 production in a MyD88-IRAK1/4 dependent manner
MyD88 inhibitory peptide significantly inhibited S. pneumoniae induced IL-23 production in a dose dependent manner, Meanwhile MyD88 control peptide did not show a significant effect on IL-23 production. When DCs were pretreated with MyD88 control peptide, morphine treatment resulted in a decrease in S. pneumoniae, LTA and PLY induced IL-23 production. However, when DCs were pretreated with MyD88 inhibitor, no difference in IL-23 production was observed between morphine and vehicle treated DCs following infection with S. pneumoniae or stimulated with LTA or PLY.
The IRAK1/4 inhibitor caused a clear reduction in IL-23 production following the infection. Pretreatment of DCs with IRAK1/4 inhibitor totally attenuated the inhibitory actions of morphine on IL-23 production following S. pneumoniae
(6)Morphine treatment modulates the phosphoralytion of ATF-2 and IRF-3 induced by infection with S. pneumoniae or stimulated with TLR2 plus Nod2 ligands
DCs were infected with S. pneumoniae or stimulated with LTA, MDP or LTA plus MDP for 45 min, then fixed and stained for the subcellular distribution of IRF-3 and ATF-2 using immune-fluorescence staining. We only detected a nuclear translocation of IRF3 and ATF2 in response to infection with S. pneumoniae, and stimulation with LTA plus MDP, or LTA alone. Morphine treatment significantly decreased the phosphorylation of IRF-3 and ATF-2.
(7)Cyclic AMP is involved in the inhibitory effects of morphine on S. pneumoniae induced IL-23 production
When compared with non-infected DCs, S. pneumoniae infection didn’t cause an alteration in levels of intracellular cAMP determined by immunoassay. Chronic morphine treatment resulted in a significant increase in intracellular cAMP in DCs. Forskolin treatment significantly inhibited IL-23 production in S. pneumoniae infected DCs, and abolished morphine’s inhibitory effect.
Conclusion
Morphine treatment causes a dysfunction in IL-23-producing dendritic cells and macrophages and IL-17-producingγδT lymphocytes in response to S. pneumoniae lung infection. This leads to diminished release of antimicrobial S100A8/A9 proteins, compromised neutrophil recruitment, and more-severe infection. Morphine impairs S. pneumoniae induced IL-23 production through MyD88-IRAK1/4-IRF3 and MyD88-IRAK1/4- ATF2 dependent TLR2 and Nod-2 synergistic signaling in DCs. Morphine-induced increase intracellular cAMP throughμ-opioid receptor may be a potential mechanism by which morphine treatment inhibits S. pneumonia infection induced IL-23 production.
引文
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