CD44-mediated monocyte transmigration across Cryptococcus neoformans-infected brain microvascular endothelial cells is enhanced by HIV-1 gp41-I90 ectodomain.
CD44-mediated monocyte transmigration across Cryptococcus neoformans-infected brain microvascular endothelial cells is enhanced by HIV-1 gp41-I90 ectodomain.
复制标题
HIV-1 gp41-I90 胞外域增强 CD44 介导的单核细胞跨新型隐球菌感染的脑微血管内皮细胞的迁移
DOI：
10.1186/s12929-016-0247-2
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发表时间：
2016-02-20
影响因子：
11
通讯作者：
Cao H
中科院分区：
文献类型：
--
作者：
He X;Shi X;Puthiyakunnon S;Zhang L;Zeng Q;Li Y;Boddu S;Qiu J;Lai Z;Ma C;Xie Y;Long M;Du L;Huang SH;Cao H
新型隐球菌（Cryptococcusneoformans，Cn）是免疫功能低下人群（包括艾滋病患者）重要的机会致病菌，可导致致死性隐球菌脑膜炎，病死率高。已有研究表明HIV-1 gp 41-I90胞外区可增强Cn对构成血脑屏障（blood brain barrier，BBB）的脑微血管内皮细胞（brain microvascular endothelial cell，BMEC）的粘附和侵袭。然而，很少有人知道HIV-1 gp 41-I90在单核细胞穿越Cn感染的血脑屏障中的作用。在本研究中，我们提供的证据表明，HIV-1 gp 41-I90和Cn协同增强单核细胞穿越血脑屏障在体外和体内。这一现象的内在机制需要进一步研究。在这项研究中，增强作用的HIV-1 gp 41-I90在单核细胞穿越Cn感染的血脑屏障的迁移证明了在体外和体内进行的迁移试验。结果表明，单核细胞的迁移率与Cn和/或HIV-1 gp 41-I90呈正相关，HIV-1 gp 41-I90 + Cn组的THP-1迁移率高于对照组（P0.01）。使用CD 44敲低的HBMEC或CD 44抑制剂Bikunin，HIV-1 gp 41-I90对单核细胞迁移率的促进作用被显著抑制。Western blotting分析和生物素/亲和素酶联免疫吸附试验（BA-ELISA）结果显示，Cn和HIV-1 gp 41-I90可增加HBMEC表面CD 44和ICAM-1的表达。此外，Cn和/或HIV-1 gp 41-I90也可诱导CD 44向膜脂筏的再分布。通过建立小鼠隐球菌性脑膜炎模型，发现HIV-1 gp 41-I90和Cn在体内可协同增强单核细胞的迁移，增加血脑屏障通透性和损伤。总之，我们的研究结果表明，HIV-1 gp 41-I90胞外域可以增强THP-1通过Cn感染的BBB的迁移，这可能是由CD 44介导的。本研究为进一步阐明HIV-1 gp 41-I90胞外域诱导的炎症反应及有效消除AIDS患者的机会性感染提供了新的思路。
Cryptococcus neoformans (Cn) is an important opportunistic pathogen in the immunocompromised people, including AIDS patients, which leads to fatal cryptococcal meningitis with high mortality rate. Previous researches have shown that HIV-1 gp41-I90 ectodomain can enhance Cn adhesion to and invasion of brain microvascular endothelial cell (BMEC), which constitutes the blood brain barrier (BBB). However, little is known about the role of HIV-1 gp41-I90 in the monocyte transmigration across Cn-infected BBB. In the present study, we provide evidence that HIV-1 gp41-I90 and Cn synergistically enhance monocytes transmigration across the BBB in vitro and in vivo. The underlying mechanisms for this phenomenon require further study. In this study, the enhancing role of HIV-1 gp41-I90 in monocyte transmigration across Cn-infected BBB was demonstrated by performed transmigration assays in vitro and in vivo. Our results showed that the transmigration rate of monocytes are positively associated with Cn and/or HIV-1 gp41-I90, the co-exposure (HIV-1 gp41-I90 + Cn) group showed a higher THP-1 transmigration rate (P < 0.01). Using CD44 knock-down HBMEC or CD44 inhibitor Bikunin in the assay, the facilitation of transmigration rates of monocyte enhanced by HIV-1 gp41-I90 was significantly suppressed. Western blotting analysis and biotin/avidin enzyme-linked immunosorbent assays (BA-ELISAs) showed that Cn and HIV-1 gp41-I90 could increase the expression of CD44 and ICAM-1 on the HBMEC. Moreover, Cn and/or HIV-1 gp41-I90 could also induce CD44 redistribution to the membrane lipid rafts. By establishing the mouse cryptococcal meningitis model, we found that HIV-1 gp41-I90 and Cn could synergistically enhance the monocytes transmigration, increase the BBB permeability and injury in vivo. Collectively, our findings suggested that HIV-1 gp41-I90 ectodomain can enhance the transmigration of THP-1 through Cn-infected BBB, which may be mediated by CD44. This novel study enlightens the future prospects to elaborate the inflammatory responses induced by HIV-1 gp41-I90 ectodomain and to effectively eliminate the opportunistic infections in AIDS patients.