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

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

Research output: Contribution to journalArticle

2 Citations (Scopus)

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.

Original languageEnglish (US)
Article number71
JournalJournal of Neuroinflammation
Volume16
Issue number1
DOIs
StatePublished - Apr 4 2019

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Purinergic Receptors
Trans-Activators
MAP Kinase Signaling System
Phosphatidylinositol 3-Kinases
Astrocytes
HIV-1
Cytokines
HIV
Apoptosis
Neurons
Cell Survival
Staining and Labeling
Viruses
Hippocampal CA1 Region
In Situ Nick-End Labeling
purinoceptor P2Y4
Small Interfering RNA
Peroxidase
HIV Infections
Fluorescent Antibody Technique

Keywords

  • Astrocytes
  • HIV-associated neurocognitive disorders
  • Inflammatory cytokines
  • Purinergic P2Y4 receptor
  • Tat

ASJC Scopus subject areas

  • Neuroscience(all)
  • Immunology
  • Neurology
  • Cellular and Molecular Neuroscience

Cite this

HIV-1 Tat enhances purinergic P2Y4 receptor signaling to mediate inflammatory cytokine production and neuronal damage via PI3K/Akt and ERK MAPK pathways. / Zhou, Feng; Liu, Xiaomei; Gao, Lin; Zhou, Xinxin; Cao, Qianwen; Niu, Liping; Wang, Jing; Zuo, Dongjiao; Li, Xiangyang; Yang, Ying; Hu, Minmin; Yu, Yinghua; Tang, Renxian; Lee, Bong Ho; Choi, Byoung Wook; Wang, Yugang; Izumiya, Yoshihiro; Xue, Min; Zheng, Kuiyang; Gao, Dianshuai.

In: Journal of Neuroinflammation, Vol. 16, No. 1, 71, 04.04.2019.

Research output: Contribution to journalArticle

Zhou, F, Liu, X, Gao, L, Zhou, X, Cao, Q, Niu, L, Wang, J, Zuo, D, Li, X, Yang, Y, Hu, M, Yu, Y, Tang, R, Lee, BH, Choi, BW, Wang, Y, Izumiya, Y, Xue, M, Zheng, K & Gao, D 2019, 'HIV-1 Tat enhances purinergic P2Y4 receptor signaling to mediate inflammatory cytokine production and neuronal damage via PI3K/Akt and ERK MAPK pathways', Journal of Neuroinflammation, vol. 16, no. 1, 71. https://doi.org/10.1186/s12974-019-1466-8
Zhou, Feng ; Liu, Xiaomei ; Gao, Lin ; Zhou, Xinxin ; Cao, Qianwen ; Niu, Liping ; Wang, Jing ; Zuo, Dongjiao ; Li, Xiangyang ; Yang, Ying ; Hu, Minmin ; Yu, Yinghua ; Tang, Renxian ; Lee, Bong Ho ; Choi, Byoung Wook ; Wang, Yugang ; Izumiya, Yoshihiro ; Xue, Min ; Zheng, Kuiyang ; Gao, Dianshuai. / HIV-1 Tat enhances purinergic P2Y4 receptor signaling to mediate inflammatory cytokine production and neuronal damage via PI3K/Akt and ERK MAPK pathways. In: Journal of Neuroinflammation. 2019 ; Vol. 16, No. 1.
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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{\circledR} 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.",
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T1 - HIV-1 Tat enhances purinergic P2Y4 receptor signaling to mediate inflammatory cytokine production and neuronal damage via PI3K/Akt and ERK MAPK pathways

AU - Zhou, Feng

AU - Liu, Xiaomei

AU - Gao, Lin

AU - Zhou, Xinxin

AU - Cao, Qianwen

AU - Niu, Liping

AU - Wang, Jing

AU - Zuo, Dongjiao

AU - Li, Xiangyang

AU - Yang, Ying

AU - Hu, Minmin

AU - Yu, Yinghua

AU - Tang, Renxian

AU - Lee, Bong Ho

AU - Choi, Byoung Wook

AU - Wang, Yugang

AU - Izumiya, Yoshihiro

AU - Xue, Min

AU - Zheng, Kuiyang

AU - Gao, Dianshuai

PY - 2019/4/4

Y1 - 2019/4/4

N2 - 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.

AB - 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.

KW - Astrocytes

KW - HIV-associated neurocognitive disorders

KW - Inflammatory cytokines

KW - Purinergic P2Y4 receptor

KW - Tat

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