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Journal of Neuroinflammation
Published in: Journal of Neuroinflammation 1/2019

Open Access 01-12-2019 | Human Immunodeficiency Virus | Research

HIV-1 Tat enhances purinergic P2Y4 receptor signaling to mediate inflammatory cytokine production and neuronal damage via PI3K/Akt and ERK MAPK pathways

Authors: Feng Zhou, Xiaomei Liu, Lin Gao, Xinxin Zhou, Qianwen Cao, Liping Niu, Jing Wang, Dongjiao Zuo, Xiangyang Li, Ying Yang, Minmin Hu, Yinghua Yu, Renxian Tang, Bong Ho Lee, Byoung Wook Choi, Yugang Wang, Yoshihiro Izumiya, Min Xue, Kuiyang Zheng, Dianshuai Gao

Published in: Journal of Neuroinflammation | Issue 1/2019

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Abstract

Background

HIV-associated neurocognitive disorders (HANDs) afflict more than half of HIV-1-positive individuals. The transactivator of transcription (Tat) produced by HIV virus elicits inflammatory process and is a major neurotoxic mediator that induce neuron damage during HAND pathogenesis. Activated astrocytes are important cells involved in neuroinflammation and neuronal damage. Purinergic receptors expressed in astrocytes participate in a positive feedback loop in virus-induced neurotoxicity. Here, we investigated that whether P2Y4R, a P2Y receptor subtype, that expressed in astrocyte participates in Tat-induced neuronal death in vitro and in vivo.

Methods

Soluble Tat protein was performed to determine the expression of P2Y4R and proinflammatory cytokines in astrocytes using siRNA technique via real-time PCR, Western blot, and immunofluorescence assays. Cytometric bead array was used to measure proinflammatory cytokine release. The TUNEL staining and MTT cell viability assay were analyzed for HT22 cell apoptosis and viability, and the ApopTag® peroxidase in situ apoptosis detection kit and cresyl violet staining for apoptosis and death of hippocampal neuron in vivo.

Results

We found that Tat challenge increased the expression of P2Y4R in astrocytes. P2Y4R signaling in astrocytes was involved in Tat-induced inflammatory cytokine production via PI3K/Akt- and ERK1/2-dependent pathways. Knockdown of P2Y4R expression significantly reduced inflammatory cytokine production and relieved Tat-mediated neuronal apoptosis in vitro. Furthermore, in vivo challenged with Tat, P2Y4R knockdown mice showed decreased inflammation and neuronal damage, especially in hippocampal CA1 region.

Conclusions

Our data provide novel insights into astrocyte-mediated neuron damage during HIV-1 infection and suggest a potential therapeutic target for HANDs.
Appendix
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Metadata
Title
HIV-1 Tat enhances purinergic P2Y4 receptor signaling to mediate inflammatory cytokine production and neuronal damage via PI3K/Akt and ERK MAPK pathways
Authors
Feng Zhou
Xiaomei Liu
Lin Gao
Xinxin Zhou
Qianwen Cao
Liping Niu
Jing Wang
Dongjiao Zuo
Xiangyang Li
Ying Yang
Minmin Hu
Yinghua Yu
Renxian Tang
Bong Ho Lee
Byoung Wook Choi
Yugang Wang
Yoshihiro Izumiya
Min Xue
Kuiyang Zheng
Dianshuai Gao
Publication date
01-12-2019
Publisher
BioMed Central
Published in
Journal of Neuroinflammation / Issue 1/2019
Electronic ISSN: 1742-2094
DOI
https://doi.org/10.1186/s12974-019-1466-8

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