ATP-induced autophagy is associated with rapid killing of intracellular mycobacteria within human monocytes/macrophages.
BMC Immunol
; 9: 35, 2008 Jul 15.
Article
en En
| MEDLINE
| ID: mdl-18627610
ABSTRACT
BACKGROUND:
We have previously reported that ATP treatment of M bovis-BCG infected human macrophages induces P2X7 receptor-dependent killing of intracellular mycobacteria. The mechanism mediating this bactericidal effect has not been full characterized but is known to be Ca2+-dependent and to promote the maturation and acidification of mycobacteria-containing phagosomes. In this study we demonstrate that the ATP/P2X7-mediated, mycobactericidal effect also involves the induction of cell autophagy.RESULTS:
We report that 3 mM ATP induces rapid cell autophagy in THP1 cells and monocyte-derived macrophages within 30 minutes post-treatment, as revealed by the expression of LC3-II bands on western blot analysis. Using Ca2+-free media and selective P2X7 agonists and antagonists, ATP-induced cell autophagy was shown to be Ca2+ and P2X7 receptor-dependent. Electron microscopy of ATP-treated, BCG-infected MDMs revealed the presence of the bacteria within characteristic double-membraned autophagosomes. Confocal analysis further confirmed that pharmacological inhibition of autophagy by wortmannin or pre-treatment of macrophages with anti-P2X7 antibody blocked ATP-induced phago-lysosomal fusion. Induction of cell autophagy with ATP was also temporally associated with a fall in intracellular mycobacterial viability, which was suppressed by treatment with wortmannin or the selective P2X7 antagonist, oxidized ATP (oATP).CONCLUSION:
We provide the first evidence that ATP/P2X7-mediated killing of intracellular mycobacteria involves the induction of cell autophagy. The findings support the hypothesis that autophagy plays a key role in the control of mycobacterial infections.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Autofagia
/
Monocitos
/
Adenosina Trifosfato
/
Receptores Purinérgicos P2
/
Macrófagos
/
Mycobacterium bovis
Tipo de estudio:
Risk_factors_studies
Límite:
Humans
Idioma:
En
Revista:
BMC Immunol
Asunto de la revista:
ALERGIA E IMUNOLOGIA
Año:
2008
Tipo del documento:
Article
País de afiliación:
Reino Unido