title: Autophagy proteins regulate innate immune responses by inhibiting the release of mitochondrial DNA mediated by the NALP3 inflammasome.
abstract: 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 1β (IL-1β) 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-1β 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.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Kiichi
authors.initials: K
authors.lastname: Nakahira
authors.forename: Jeffrey Adam
authors.initials: JA
authors.lastname: Haspel
authors.forename: Vijay A K
authors.initials: VA
authors.lastname: Rathinam
authors.forename: Seon-Jin
authors.initials: SJ
authors.lastname: Lee
authors.forename: Tamas
authors.initials: T
authors.lastname: Dolinay
authors.forename: Hilaire C
authors.initials: HC
authors.lastname: Lam
authors.forename: Joshua A
authors.initials: JA
authors.lastname: Englert
authors.forename: Marlene
authors.initials: M
authors.lastname: Rabinovitch
authors.forename: Manuela
authors.initials: M
authors.lastname: Cernadas
authors.forename: Hong Pyo
authors.initials: HP
authors.lastname: Kim
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Fitzgerald
authors.forename: Stefan W
authors.initials: SW
authors.lastname: Ryter
authors.forename: Augustine M K
authors.initials: AM
authors.lastname: Choi
mesh_terms: D000818:Animals; D001343:Autophagy; D002352:Carrier Proteins / Q000276:immunology*; D020170:Caspase 1 / Q000276:immunology; D004272:DNA, Mitochondrial; D005434:Flow Cytometry; D007113:Immunity, Innate; D058847:Inflammasomes / Q000276:immunology*; D051379:Mice; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein
chemical_list: D002352:Carrier Proteins; D004272:DNA, Mitochondrial; D058847:Inflammasomes; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; D020170:Caspase 1