A central role for glial CCR5 in directing the neuropathological interactions of HIV-1 Tat and opiates.
A central role for glial CCR5 in directing the neuropathological interactions of HIV-1 Tat and opiates.
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DOI：
10.1186/s12974-018-1320-4
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发表时间：
2018-10-10
影响因子：
9.3
通讯作者：
Knapp PE
中科院分区：
文献类型：
--
作者：
Kim S;Hahn YK;Podhaizer EM;McLane VD;Zou S;Hauser KF;Knapp PE
即使在抗逆转录病毒治疗得到优化的HIV+个体中，被称为HIV相关神经认知障碍（HAND）的集体认知和运动缺陷仍然很高。在阿片类药物滥用的情况下，HAND会恶化。恶化的机制尚不清楚，但可能与持续低水平暴露于病毒和病毒蛋白导致的神经胶质细胞的慢性免疫激活有关。我们测试了通过C-C趋化因子受体5型（CCR5）传递的信号是否有助于HIV-1转录反激活因子（Tat）和阿片类药物之间的神经毒性相互作用，并探索了潜在的机制。使用暴露于CCR5拮抗剂马拉维roc或外源添加BDNF的CCR5缺陷小鼠和野生型小鼠的细胞，用HIV-1 Tat±吗啡治疗神经元和胶质共培养72小时后，追踪神经元存活情况（通过重复测量方差分析进行分析）。采用比值法Fura-2显像（采用重复测量方差分析）评估泰±吗啡±马拉韦洛克对细胞内钙的影响。采用ELISA检测ccr5缺失和野生型胶质细胞中脑源性神经营养因子（BDNF）及其前体proBDNF的释放（采用双因素方差分析）。免疫印迹法检测CCR5和μ-阿片受体（MOR）水平（学生t检验）。在表达CCR5的野生型培养物中，吗啡极大地加重了HIV-1 Tat的神经毒性。神经胶质细胞（而非神经元）中CCR5的缺失消除了因Tat和吗啡相互作用而产生的神经毒性。出乎意料的是，当CCR5从神经胶质细胞中丢失时，吗啡似乎完全保护神经元免受tat诱导的毒性。马拉韦洛克预处理同样消除了神经毒性，并减弱了由吗啡引起的[Ca2+]i神经元的增加。与ccr5缺失的胶质细胞相比，Tat±吗啡处理的野生型胶质细胞在条件培养基中proBDNF/BDNF比率增加。外源性BDNF治疗模拟了神经胶质CCR5缺乏对吗啡的促生存作用。我们的研究结果表明，神经胶质CCR5在介导HIV-1 Tat和吗啡相互作用对神经元的神经毒性作用中起关键作用。当神经胶质CCR5信号被阻断时，proBDNF/BDNF比例的改变可能有利于神经营养支持。一些神经保护仅在吗啡存在的情况下发生，这表明CCR5的缺失可能从根本上改变了神经胶质中MOR的信号传导。
The collective cognitive and motor deficits known as HIV-associated neurocognitive disorders (HAND) remain high even among HIV+ individuals whose antiretroviral therapy is optimized. HAND is worsened in the context of opiate abuse. The mechanism of exacerbation remains unclear but likely involves chronic immune activation of glial cells resulting from persistent, low-level exposure to the virus and viral proteins. We tested whether signaling through C-C chemokine receptor type 5 (CCR5) contributes to neurotoxic interactions between HIV-1 transactivator of transcription (Tat) and opiates and explored potential mechanisms. Neuronal survival was tracked in neuronal and glial co-cultures over 72 h of treatment with HIV-1 Tat ± morphine using cells from CCR5-deficient and wild-type mice exposed to the CCR5 antagonist maraviroc or exogenously-added BDNF (analyzed by repeated measures ANOVA). Intracellular calcium changes in response to Tat ± morphine ± maraviroc were assessed by ratiometric Fura-2 imaging (analyzed by repeated measures ANOVA). Release of brain-derived neurotrophic factor (BDNF) and its precursor proBDNF from CCR5-deficient and wild-type glia was measured by ELISA (analyzed by two-way ANOVA). Levels of CCR5 and μ-opioid receptor (MOR) were measured by immunoblotting (analyzed by Student’s t test). HIV-1 Tat induces neurotoxicity, which is greatly exacerbated by morphine in wild-type cultures expressing CCR5. Loss of CCR5 from glia (but not neurons) eliminated neurotoxicity due to Tat and morphine interactions. Unexpectedly, when CCR5 was lost from glia, morphine appeared to entirely protect neurons from Tat-induced toxicity. Maraviroc pre-treatment similarly eliminated neurotoxicity and attenuated neuronal increases in [Ca2+]i caused by Tat ± morphine. proBDNF/BDNF ratios were increased in conditioned media from Tat ± morphine-treated wild-type glia compared to CCR5-deficient glia. Exogenous BDNF treatments mimicked the pro-survival effect of glial CCR5 deficiency against Tat ± morphine. Our results suggest a critical role for glial CCR5 in mediating neurotoxic effects of HIV-1 Tat and morphine interactions on neurons. A shift in the proBDNF/BDNF ratio that favors neurotrophic support may occur when glial CCR5 signaling is blocked. Some neuroprotection occurred only in the presence of morphine, suggesting that loss of CCR5 may fundamentally change signaling through the MOR in glia.
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DOI：
10.1097/qai.0b013e318229ba41
发表时间：
2011-10-01
期刊：
Journal of acquired immune deficiency syndromes (1999)
影响因子：
--
作者：
Byrd DA;Fellows RP;Morgello S;Franklin D;Heaton RK;Deutsch R;Atkinson JH;Clifford DB;Collier AC;Marra CM;Gelman B;McCutchan JA;Duarte NA;Simpson DM;McArthur J;Grant I;CHARTER Group
通讯作者：
CHARTER Group
影响因子：
6.2
作者：
El-Hage, Nazira;Bruce-Keller, Annadora J.;Knapp, Pamela E.;Hauser, Kurt F.
通讯作者：
Hauser, Kurt F.
DOI：
10.1097/qad.0b013e3283639804
发表时间：
2013-09-10
期刊：
AIDS (London, England)
影响因子：
--
作者：
El-Hage N;Dever SM;Podhaizer EM;Arnatt CK;Zhang Y;Hauser KF
通讯作者：
Hauser KF
影响因子：
11.2
作者：
Churchill, Melissa J.;Wesselingh, Steven L.;Gorry, Paul R.
通讯作者：
Gorry, Paul R.
影响因子：
12.7
作者：
An, SF;Groves, M;Scaravilli, F
通讯作者：
Scaravilli, F