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TLR-Activated Gap Junction Channels Protect Mice against Bacterial Infection through Extracellular UDP Release

Juliang Qin, Guangxu Zhang, Xiaoyu Zhang, Binghe Tan, Zhangsheng Lv, Mingyao Liu, Hua Ren, Min Qian and Bing Du
J Immunol February 15, 2016, 196 (4) 1790-1798; DOI: https://doi.org/10.4049/jimmunol.1501629
Juliang Qin
Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai 200241, China
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Guangxu Zhang
Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai 200241, China
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Xiaoyu Zhang
Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai 200241, China
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Binghe Tan
Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai 200241, China
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Zhangsheng Lv
Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai 200241, China
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Mingyao Liu
Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai 200241, China
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Hua Ren
Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai 200241, China
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Min Qian
Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai 200241, China
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Bing Du
Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai 200241, China
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Abstract

Extracellular UDP (eUDP), released as a danger signal by stressed or apoptotic cells, plays an important role in a series of physiological processes. Although the mechanism of eUDP release in apoptotic cells has been well defined, how the eUDP is released in innate immune responses remains unknown. In this study, we demonstrated that UDP was released in both Escherichia coli–infected mice and LPS- or Pam3CSK4-treated macrophages. Also, LPS-induced UDP release could be significantly blocked by selective TLR4 inhibitor Atractylenolide I and selective gap junction inhibitors carbenoxolone and flufenamic acid (FFA), suggesting the key role of TLR signaling and gap junction channels in this process. Meanwhile, eUDP protected mice from peritonitis by reducing invaded bacteria that could be rescued by MRS2578 (selective P2Y6 receptor inhibitor) and FFA. Then, connexin 43, as one of the gap junction proteins, was found to be clearly increased by LPS in a dose- and time-dependent manner. Furthermore, if we blocked LPS-induced ERK signaling by U0126, the expression of connexin 43 and UDP release was also inhibited dramatically. In addition, UDP-induced MCP-1 secretion was significantly reduced by MRS2578, FFA, and P2Y6 mutation. Accordingly, pretreating mice with U0126 and Gap26 increased invaded bacteria and aggravated mice death. Taken together, our study reveals an internal relationship between danger signals and TLR signaling in innate immune responses, which suggests a potential therapeutic significance of gap junction channel–mediated UDP release in infectious diseases.

Footnotes

  • This work was supported by National Basic Research Program of China Grant 2012CB910404; National Natural Science Foundation of China Grants 81272369, 81172816, and 31570896; Ministry of Education of China Doctoral Fund 20130076110013; Fundamental Research Funds for the Central Universities; and Science and Technology Commission of Shanghai Municipality Grant 15JC1401500.

  • Abbreviations used in this article:

    AOI
    atractylenolide I
    BMM
    bone marrow–derived macrophage
    CBX
    carbenoxolone
    DAMP
    damage-associated molecular pattern
    eUDP
    extracellular UDP
    FFA
    flufenamic acid
    GJC
    gap junction channel
    LB
    Luria–Bertani
    PAMP
    pathogen-associated molecular pattern
    WT
    wild-type.

  • Received July 21, 2015.
  • Accepted December 16, 2015.
  • Copyright © 2016 by The American Association of Immunologists, Inc.
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The Journal of Immunology: 196 (4)
The Journal of Immunology
Vol. 196, Issue 4
15 Feb 2016
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TLR-Activated Gap Junction Channels Protect Mice against Bacterial Infection through Extracellular UDP Release
Juliang Qin, Guangxu Zhang, Xiaoyu Zhang, Binghe Tan, Zhangsheng Lv, Mingyao Liu, Hua Ren, Min Qian, Bing Du
The Journal of Immunology February 15, 2016, 196 (4) 1790-1798; DOI: 10.4049/jimmunol.1501629

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TLR-Activated Gap Junction Channels Protect Mice against Bacterial Infection through Extracellular UDP Release
Juliang Qin, Guangxu Zhang, Xiaoyu Zhang, Binghe Tan, Zhangsheng Lv, Mingyao Liu, Hua Ren, Min Qian, Bing Du
The Journal of Immunology February 15, 2016, 196 (4) 1790-1798; DOI: 10.4049/jimmunol.1501629
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