p53 signalling controls cell cycle arrest and caspase-independent apoptosis in macrophages infected with pathogenic Leptospira species

Authors

  • Weilin Hu,

    1. Division of Basic Medical Microbiology, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
    2. Department of Medical Microbiology and Parasitology, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
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    • Both authors contributed equally to this work.
  • Yumei Ge,

    1. Department of Medical Microbiology and Parasitology, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
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    • Both authors contributed equally to this work.
  • David M. Ojcius,

    1. Health Sciences Research Institute and Molecular Cell Biology, University of California, Merced, CA, USA
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  • Dexter Sun,

    1. Department of Neurology and Neuroscience, New York Presbyterian Hospital and Hospital for Special Surgery, Cornell University Weill Medical College, New York, NY, USA
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  • Haiyan Dong,

    1. Department of Medical Microbiology and Immunology, Wenzhou Medical College, Wenzhou, Zhejiang, China
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  • X. Frank Yang,

    Corresponding author
    • Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, USA
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  • Jie Yan

    Corresponding author
    1. Department of Medical Microbiology and Parasitology, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
    • Division of Basic Medical Microbiology, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
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For correspondence. E-mail Med_bp@zju.edu.cn; Tel. (+86) 571 88208297; Fax (+86) 571 88208294; E-mail xfyang@iupui.edu; Tel. (+1) 317 274 8691; Fax (+1) 317 274 4090.

Summary

Pathogenic Leptospira species, the causative agents of leptospirosis, have been shown to induce macrophage apoptosis through caspase-independent, mitochondrion-related apoptosis inducing factor (AIF) and endonuclease G (EndoG), but the signalling pathway leading to AIF/EndoG-based macrophage apoptosis remains unknown. Here we show that infection of Leptospira interrogans caused a rapid increase in reactive oxygen species (ROS), DNA damage, and intranuclear foci of 53BP1 and phosphorylation of H2AX (two DNAdamage indicators) in wild-type p53-containing mouse macrophages and p53-deficient human macrophages. Most leptospire-infected cells stayed at the G1 phase, whereas depletion or inhibition of p53 caused a decrease of the G1-phase cells and the early apoptotic ratios. Infection with spirochaetes stimulated a persistent activation of p53 and an early activation of Akt through phosphorylation. The intranuclear translocation of p53, increased expression of p53-dependent p21Cip1/WAF1 and pro-apoptotic Bcl-2 family proteins (Bax, Noxa and Puma), release of AIF and EndoG from mitochondria, and membrane translocation of Fas occurred during leptospire-induced macrophage apoptosis. Thus, our study demonstrated that ROS production and DNA damage-dependent p53-Bax/Noxa/Puma-AIF/EndoG signalling mediates the leptospire-induced cell cycle arrest and caspase-independent apoptosis of macrophages.

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