Both authors contributed equally to this work.
p53 signalling controls cell cycle arrest and caspase-independent apoptosis in macrophages infected with pathogenic Leptospira species
Article first published online: 9 APR 2013
© 2013 John Wiley & Sons Ltd
Volume 15, Issue 10, pages 1624–1659, October 2013
How to Cite
Hu, W., Ge, Y., Ojcius, D. M., Sun, D., Dong, H., Yang, X. F. and Yan, J. (2013), p53 signalling controls cell cycle arrest and caspase-independent apoptosis in macrophages infected with pathogenic Leptospira species. Cellular Microbiology, 15: 1624–1659. doi: 10.1111/cmi.12141
- Issue published online: 15 SEP 2013
- Article first published online: 9 APR 2013
- Accepted manuscript online: 21 MAR 2013 11:20PM EST
- Manuscript Accepted: 14 MAR 2013
- Manuscript Revised: 7 MAR 2013
- Manuscript Received: 1 JUL 2012
- National Natural Science Foundation of China. Grant Numbers: 81171534, 81261160321
- National Key Laboratory for Diagnosis and Treatment of Infectious Diseases of China. Grant Number: 2010ZZ09
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.