Toll-Like Receptor-3 Mediates HIV-1-Induced Interleukin-6 Expression in the Human Brain Endothelium via TAK1 and JNK Pathways: Implications for Viral Neuropathogenesis.
Toll-Like Receptor-3 Mediates HIV-1-Induced Interleukin-6 Expression in the Human Brain Endothelium via TAK1 and JNK Pathways: Implications for Viral Neuropathogenesis.
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DOI：
10.1007/s12035-017-0816-8
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发表时间：
2018-07
影响因子：
5.1
通讯作者：
Kanmogne GD
中科院分区：
文献类型：
--
作者：
Bhargavan B;Kanmogne GD
hiv -1相关的神经认知障碍（HAND）与血脑屏障（BBB）炎症有关，炎症涉及toll样受体（TLRs）信号传导。目前尚不清楚作为血脑屏障主要成分的人脑微血管内皮细胞（HBMEC）是否表达tlr，以及tlr是否参与血脑屏障功能障碍和HAND。我们发现HBMEC表达TLR3、4、5、7、9和10，其中TLR3最丰富。HIV-1和TLR3的激活增加了内皮TLR3的转录和表达。hiv -1阳性的人类受试者脑组织和血管中TLR3的表达明显升高，而HAND患者的TLR3表达水平更高。HIV-1和TLR3激活使内皮细胞IL6的表达增加了6- 127倍（P<0.001），激活了c-jun（丝氨酸-63）和SAPK/JNK（Thr183/Tyr185）。HIV-1通过白细胞介素-1受体相关激酶(IRAK)-1/4/TAK1/JNK通路上调il - 6，通过atp依赖性JNK激活。TLR3激活通过TAK1/JNK途径，通过atp依赖性或非依赖性JNK激活上调IL6。HIV-1和TLR3的激活也上调了与IL6和TAK1/JNK通路相关的转录因子（Jun， CEBPA, STAT1）。阻断TLR3激活可以阻止hiv -1和TLR3配体诱导的这些转录因子的上调，阻止IL6的转录和表达、c-jun和JNK的激活。HIV-1和TLR3配体显著增加单核细胞通过血脑屏障的粘附和迁移，降低内皮细胞claudin-5的表达。阻断TLR3和JNK激活可阻止HIV-1和TLR3配体诱导的claudin-5下调、单核细胞粘附和跨内皮迁移。这些数据表明，通过内皮TLR3的病毒免疫识别参与了HIV/AIDS和HAND的内皮炎症和血脑屏障功能障碍。我们的数据为这些HIV-1和tlr3介导效应的分子基础提供了新的见解。
HIV-1-associated neurocognitive impairment (HAND) is associated with blood-brain-barrier (BBB) inflammation, and inflammation involves toll-like receptors (TLRs) signaling. It is not known whether primary human brain microvascular endothelial cells (HBMEC), the major BBB component, express TLRs or whether TLRs are involved in BBB dysfunction and HAND. We demonstrate that HBMEC express TLR3, 4, 5, 7, 9, and 10, and TLR3 was the most abundant. HIV-1 and TLR3 activation increased endothelial TLR3 transcription and expression. HIV-1-positive human subjects showed significantly higher TLR3 expression in brain tissues and blood vessels, with higher TLR3 levels in subjects with HAND. HIV-1 and TLR3 activation increased endothelial IL6 expression by 6-to-127-fold (P<0.001), activated c-jun(serine-63) and SAPK/JNK(Thr183/Tyr185). HIV-1 upregulated IL6 through interleukin-1 receptor-associated-kinase(IRAK)-1/4/TAK1/JNK pathways, via ATP-dependent JNK activation. TLR3 activation upregulated IL6 through TAK1/JNK pathways, via ATP-dependent or -independent JNK activation. HIV-1 and TLR3 activation also upregulated transcription factors associated with IL6 and TAK1/JNK pathways (Jun, CEBPA, STAT1). Blocking TLR3 activation prevented HIV-1-and TLR3 ligands-induced upregulation of these transcription factors, prevented IL6 transcription and expression, c-jun and JNK activation. HIV-1 and TLR3 ligands significantly increased monocytes adhesion and migration through the BBB, and decreased endothelial claudin-5 expression. Blocking TLR3 and JNK activation prevented HIV-1- and TLR3 ligands-induced claudin-5 downregulation, monocytes adhesion and transendothelial migration. These data suggests that viral immune recognition via endothelial TLR3 is involved in endothelial inflammation and BBB dysfunction in HIV/AIDS and HAND. Our data provides novel insights into the molecular basis of these HIV-1- and TLR3-mediated effects.
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影响因子：
16.8
作者：
Hanamsagar R;Hanke ML;Kielian T
通讯作者：
Kielian T
影响因子：
64.8
作者：
Alexopoulou, L;Holt, AC;Flavell, RA
通讯作者：
Flavell, RA
影响因子：
4.8
作者：
Bhargavan B;Woollard SM;Kanmogne GD
通讯作者：
Kanmogne GD
影响因子：
1.5
作者：
Buitendijk, Maarten;Eszterhas, Susan K.;Howell, Alexandra L.
通讯作者：
Howell, Alexandra L.
DOI：
10.1073/pnas.0603245103
发表时间：
2006-06-06
影响因子：
11.1
作者：
Bell, Jessica K.;Askins, Janine;Segal, David M.
通讯作者：
Segal, David M.