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

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Evaluation of Caspase Activation to Assess Innate Immune Cell Death
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Weilin Hu1, Yumei Ge, David M Ojcius

  • 1Division of Basic Medical Microbiology, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310003, China; Department of Medical Microbiology and Parasitology, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310058, China.

Cellular Microbiology
|March 26, 2013
PubMed

Insights

Pathogenic Leptospira bacteria trigger macrophage death via a pathway involving reactive oxygen species (ROS) and DNA damage. This process activates p53, leading to caspase-independent apoptosis mediated by apoptosis inducing factor (AIF) and endonuclease G (EndoG).

Area of Science:

  • Microbiology
  • Cell Biology
  • Immunology

Background:

  • Pathogenic Leptospira species cause leptospirosis, inducing macrophage apoptosis via caspase-independent pathways involving apoptosis inducing factor (AIF) and endonuclease G (EndoG).
  • The precise signaling cascade initiating AIF/EndoG-mediated macrophage apoptosis during Leptospira infection is not fully understood.

Purpose of the Study:

  • To elucidate the signaling pathway responsible for Leptospira-induced, caspase-independent macrophage apoptosis.
  • To investigate the roles of reactive oxygen species (ROS), DNA damage, and p53 in this apoptotic process.

Main Methods:

  • Infection of mouse and human macrophages with Leptospira interrogans.
  • Assessment of ROS production, DNA damage markers (53BP1, H2AX phosphorylation), cell cycle progression, and apoptosis.
  • Analysis of p53 activation, Akt phosphorylation, and the expression/translocation of key proteins including p21, Bax, Noxa, Puma, AIF, EndoG, and Fas.

Main Results:

  • Leptospira infection rapidly increased ROS, induced DNA damage, and caused G1 cell cycle arrest in macrophages.
  • p53 activation was sustained, while Akt phosphorylation occurred early; p53 depletion reduced G1 arrest and apoptosis.
  • Intranuclear p53 translocation, increased p21 and pro-apoptotic protein expression (Bax, Noxa, Puma), mitochondrial release of AIF/EndoG, and Fas translocation were observed.

Conclusions:

  • Leptospira-induced macrophage apoptosis is mediated by a signaling pathway involving ROS production and DNA damage.
  • This pathway is dependent on p53 activation, leading to the upregulation of Bax/Noxa/Puma and subsequent caspase-independent apoptosis via AIF/EndoG release.

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