Does drug abuse alter microglial phenotype and cell turnover in the context of advancing HIV infection?
Does drug abuse alter microglial phenotype and cell turnover in the context of advancing HIV infection?
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DOI：
10.1111/j.1365-2990.2005.00648.x
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发表时间：
2005-06-01
影响因子：
5
通讯作者：
Bell, JE
中科院分区：
文献类型：
--
作者：
Anthony, IC;Ramage, SN;Bell, JE
本研究的目的是测试药物滥用，特别是阿片类药物滥用，在推进艾滋病毒感染的背景下，对大脑内的小胶质细胞的表型和营业额的影响。对51例HIV阴性正常人、HIV阴性吸毒者、AIDS非吸毒者、AIDS吸毒者、HIV脑炎（HIVE）非吸毒者和HIVE吸毒者的基底节和海马进行了脑组织切片观察。研究的病例中没有一个接受过高效抗逆转录病毒治疗（HAART）。使用CD 14、CD 16、CD 68和主要组织相容性II类（MHC II）定义小胶质细胞表型。使用末端脱氧核苷酸转移酶介导的dUTP缺口末端标记（TUNEL）（DNA损伤）、BAX（促凋亡标志物）、Fas（CD 95）（促凋亡）、增殖细胞核抗原（PCNA）（增殖和DNA修复）、Ki-67（细胞增殖）和BCL-2（抗凋亡）评估小胶质细胞更新。我们发现增加的表达MHC II和CD 16的药物滥用。我们还注意到，与非药物滥用者相比，药物滥用者的TUNEL阳性水平增加，尽管相反，我们发现滥用药物者的BAX水平较低。我们在任何研究组（包括HIVE）中均未发现小胶质细胞增殖的证据，尽管HIV感染导致CD 16、CD 68和MHC II表达增加。除了两个HIVE组（其中一些但不是所有病例也显示实质表达CD 14）外，所有组（包括正常对照组）中CD 14表达仅限于血管周围小胶质细胞。相反，在所有组的实质小胶质细胞中发现了CD 16。使用高压抗原修复和酪胺信号放大，我们发现适度高水平的CD 16表达在正常脑实质中，这是不正常的观察使用标准的抗生物素蛋白/生物素复合物（ABC）技术。这表明CD 16的低基础表达发生在许多驻留的小胶质细胞中，其可能在HIV感染个体中上调。从这些数据，我们认为，并不是所有的CD 16+实质细胞检测到艾滋病的大脑（使用ABC）代表流入单核细胞谱系细胞从血液。最后，与非药物滥用者相比，在药物滥用者中检测到的MHC II和CD 68的表达增加表明药物滥用和HIV感染的结合对大脑的有害影响比单独的伤害更大。
The aim of this study was to test the effects of drug abuse, in particular opiate abuse, on the phenotype and turnover of microglial cells within the brain in the context of advancing HIV infection. Basal ganglia and hippocampus sections were studied in 51 cases divided into six groups: HIV-negative normal controls, HIV-negative drug abusers, AIDS nondrug abusers, AIDS drug abusers, HIV encephalitis (HIVE) nondrug abusers and HIVE drug abusers. None of the cases studied had received highly active anti-retroviral therapy (HAART). Microglial phenotypes were defined using CD14, CD16, CD68 and major histocompatibility class II (MHC II). Microglial turnover was assessed using terminal deoxynucleotidyl transferase mediated dUTP nick end labelling (TUNEL) (DNA damage), BAX (proapoptotic marker), Fas (CD95) (proapoptotic), proliferating cell nuclear antigen (PCNA) (proliferation and DNA repair), Ki-67 (cell proliferation) and BCL-2 (antiapoptosis). We find increased expression of MHC II and CD16 in response to drug abuse. We also noted increased levels of TUNEL positivity in drug abusers compared to nondrug abusers, although conversely we found lower levels of BAX in those who had abused drugs. We find no evidence of microglial proliferation in any of our study groups, including HIVE, although HIV infection leads to increased expression of CD16, CD68 and MHC II. CD14 expression was restricted to perivascular microglia in all groups (including normal controls) apart from the two HIVE groups where some but not all cases also showed parenchymal expression of CD14. In contrast, CD16 was found in parenchymal microglia in all groups. Using high-pressure antigen retrieval and tyramide signal amplification, we find moderately high levels of CD16 expression in the parenchyma of normal brains which is not normally observed using standard avidin/biotin complex (ABC) techniques. This suggests that a low basal expression of CD16 occurs in many resident microglial cells which may potentially be upregulated in HIV-infected individuals. From these data, we suggest that not all the CD16+ parenchymal cells detected in AIDS brains (using ABC) represent influx of monocyte lineage cells from the blood. Finally the increased expression of MHC II and CD68 detected in drug abusers with HIVE compared to nondrug abusers with HIVE suggests that the combination of drug abuse and HIV infection has a greater deleterious effect on the brain than either individual insult on its own.