Human immunodeficiency virus-1 Tat exerts its neurotoxic effects by downregulating Sonic hedgehog signaling.
Human immunodeficiency virus-1 Tat exerts its neurotoxic effects by downregulating Sonic hedgehog signaling.
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DOI：
10.1007/s13365-022-01061-8
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发表时间：
2022-04
影响因子：
3.2
通讯作者：
Singh, Vir B.
中科院分区：
文献类型：
--
作者：
Khan, Irfan A.;Worrad, Arthur H.;Singh, Meera, V;Maggirwar, Sanjay B.;Singh, Vir B.
关键词：
我们之前的研究表明，HIV-1可以通过下调Sonic hedgehog （Shh）信号来改变紧密连接蛋白的表达，从而破坏血脑屏障（BBB）的完整性。在这项研究中，我们采用了一种有条件的、中枢神经系统特异性的Tat转基因小鼠模型来研究HIV-Tat是否通过下调Shh信号来发挥其神经毒性作用。结果表明Tat +小鼠的Shh和Gli1的表达显著降低。HIV-Tat诱导的Shh信号下调与血脑屏障功能破坏和诱导外周白细胞渗入脑组织相关。此外，我们的体内和体外实验表明，Shh信号的激活可以通过诱导连接蛋白的表达和降低炎症细胞因子/趋化因子的水平来挽救Tat对内皮功能的有害影响。
We previously showed that HIV-1 can alter the expression of tight junction proteins by downregulating Sonic hedgehog (Shh) signaling, thereby disrupting blood–brain barrier (BBB) integrity. In this study, we employed a conditional, CNS specific, Tat transgenic murine model to investigate if HIV-Tat exerts its neurotoxic effects by downregulating Shh signaling. Results indicate that Tat + mice exhibit significantly reduced expression of Shh and Gli1. HIV-Tat induced downregulation of Shh signaling correlated with disruption of BBB function and induced infiltration of peripheral leukocytes into the brain tissue. Further, our in vivo and in vitro experiments suggest that activation of Shh signaling can rescue detrimental effects of Tat on endothelial function by inducing the expression of junctional proteins and by decreasing the levels of inflammatory cytokines/chemokines.
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通讯作者：
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