Alpha7 nicotinic acetylcholine receptor is required for blood-brain barrier injury-related CNS disorders caused by Cryptococcus neoformans and HIV-1 associated comorbidity factors.
Alpha7 nicotinic acetylcholine receptor is required for blood-brain barrier injury-related CNS disorders caused by Cryptococcus neoformans and HIV-1 associated comorbidity factors.
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由新型隐球菌和 HIV-1 相关合并症因素引起的血脑屏障损伤相关中枢神经系统疾病需要 Alpha7 烟碱乙酰胆碱受体
DOI：
10.1186/s12879-015-1075-9
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发表时间：
2015-08-19
影响因子：
3.7
通讯作者：
Huang SH
中科院分区：
文献类型：
--
作者：
Zhang B;Yu JY;Liu LQ;Peng L;Chi F;Wu CH;Jong A;Wang SF;Cao H;Huang SH
背景：隐球菌性脑膜炎是HIV/AIDS中最常见的中枢神经系统真菌感染。HIV-1病毒毒素（例如，gp 41）能够诱导主要由BMEC组成的血脑屏障（BBB）的障碍。我们最近的研究表明，α7 nAChR是炎症的重要调节因子，其有助于调节NF-κB信号传导、神经炎症和由微生物（例如，HIV-1 gp 120）和非微生物[例如，甲基苯丙胺（METH）因素。然而，多种合并症的潜在机制尚不清楚。方法：在这份报告中，α7 nAChR在宿主防御这些合并症引起的中枢神经系统疾病的加重作用被证明是由化学[抑制剂：甲基乌头碱（MLA）]和遗传（α7（-/-）小鼠）阻断α7 nAChR.Results：如我们在体内研究中所示，BBB损伤显着减少在α7（-/-）小鼠感染C。新人类在α7（-/-）动物中消除了gp 41胞外域肽（gp 41-I90）和METH的刺激。C. gp 41-I90可激活NF-κB B。MLA和CAPE（咖啡酸苯乙酯，NF-κB抑制剂）可显著抑制Gp 41-I90和MET诱导的单核细胞迁移和衰老。新生儿和HIV-1相关的共病因子诱导的BBB损伤和CNS疾病。
Background:Cryptococcal meningitis is the most common fungal infection of the central nervous system (CNS) in HIV/AIDS. HIV-1 virotoxins (e.g., gp41) are able to induce disorders of the blood-brain barrier (BBB), which mainly consists of BMEC. Our recent study suggests that α7 nAChR is an essential regulator of inflammation, which contributes to regulation of NF-κB signaling, neuroinflammation and BBB disorders caused by microbial (e.g., HIV-1 gp120) and non-microbial [e.g., methamphetamine (METH)] factors. However, the underlying mechanisms for multiple comorbidities are unclear.Methods:In this report, an aggravating role of α7 nAChR in host defense against CNS disorders caused by these comorbidities was demonstrated by chemical [inhibitor: methyllycaconitine (MLA)] and genetic (α7(-/-) mice) blockages of α7 nAChR.Results:As shown in our in vivo studies, BBB injury was significantly reduced in α7(-/-) mice infected with C. neoformans. Stimulation by the gp41 ectodomain peptide (gp41-I90) and METH was abolished in the α7(-/-) animals. C. neoformans and gp41-I90 could activate NF-κB. Gp41-I90- and METH-induced monocyte transmigration and senescence were significantly inhibited by MLA and CAPE (caffeic acid phenethyl ester, an NF-κB inhibitor).Conclusions:Collectively, our data suggest that α7 nAChR plays a detrimental role in the host defense against C. neoformans- and HIV-1 associated comorbidity factors-induced BBB injury and CNS disorders.