Autophagy proteins regulate innate immune responses by inhibiting the release of mitochondrial DNA mediated by the NALP3 inflammasome

Kiichi Nakahira, et al. 2011. Nat. Immunol. 12: 222-30.

Speaker: Shu-Ting Lu (呂淑婷)                                    Time: 13:00~14:00, Nov. 7, 2012

Commentator: Dr. Chih-Peng Chang (張志鵬 老師)  Place: Room 601

Abstract:

Autophagy is a cellular catabolic mechanism that involves cell degradation of unnecessary or dysfunctional cellular components, as well as intracellular pathogens through the lysosomal machinery. Inflammasome is a cytoplasmic multiprotein complex assembled to activate pro-caspase-1, in order to cleave and secret proinflammatory cytokines, such as IL-1β and IL-18. Mitochondrion is an organelle that generates cellular energy which performs redox reactions. Previous studies show that the deficiency of autophagic proteins can regulate inflammasome activity and reduce IL-1β production (1). The authors tried to clarify the mechanism how autophagic proteins regulate the activity of inflammasome. After stimuli with LPS and ATP, they observed more severe mitochondrial destroy in bone marrow-derived macrophages from autophagic deficient (LC3b^-/- and beclin 1^+/-) mice. They also found that autophagic deficient macrophages product more mitochondrial ROS (mtROS) which augments caspase-1 activity and secrets more IL-1β and IL-18. As membrane permeability transition (MPT) is dependent on mtROS production (2), they found that more caspase-1 activation in autophagic protein-deficient cells which accompanied by mitochondrial DNA  (mtDNA) release through MPT, and both of them were dependent on mtROS generation. Furthermore, cytosol mtDNA serve as a coactivator of caspase-1 and was mediated by NALP3 inflammasome, as well, the mtDNA induced caspase-1 was also activated by NALP3 inflammasome. Finally, in the two sepsis animal models, they observed that the serum concentrations of IL-1β and IL-18 in autophagy-deficient mice were significantly higher than wild type mice and were more susceptible to sepsis-induced mortality. In conclusion, this study indicates mitochondria orchestrate the innate immune response which links between autophagy and inflammasome activation.

References:

1.      Saitoh, T., et al. 2008. Loss of the autophagy protein Atg16L1 enhances endotoxin-induced IL-1β production. Nature 456, 264–268.

2.      Lemasters, J.J., et al. 2009. Mitochondrial calcium and the permeability transition in cell death. Biochim. Biophys. Acta 1787, 1395–1401.