期刊
NATURE IMMUNOLOGY
卷 12, 期 3, 页码 222-U57出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/ni.1980
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资金
- National Institutes of Health [HL079904-12, HL08554, HL060234-10, HL097005, AI083713, AI067497]
- New England Regional Center of Excellence for Biodefense and Emerging Infectious Diseases (National Institute of Allergy and Infectious Diseases of the National Institutes of Health) [AI057159]
Autophagy, a cellular process for organelle and protein turnover, regulates innate immune responses. Here we demonstrate that depletion of the autophagic proteins LC3B and beclin 1 enhanced the activation of caspase-1 and secretion of interleukin 1 (IL-1 beta) and IL-18. Depletion of autophagic proteins promoted the accumulation of dysfunctional mitochondria and cytosolic translocation of mitochondrial DNA (mtDNA) in response to lipopolysaccharide (LPS) and ATP in macrophages. Release of mtDNA into the cytosol depended on the NALP3 inflammasome and mitochondrial reactive oxygen species (ROS). Cytosolic mtDNA contributed to the secretion of IL-1 beta and IL-18 in response to LPS and ATP. LC3B-deficient mice produced more caspase-1-dependent cytokines in two sepsis models and were susceptible to LPS-induced mortality. Our study suggests that autophagic proteins regulate NALP3-dependent inflammation by preserving mitochondrial integrity.
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