title: ATP release from dying autophagic cells and their phagocytosis are crucial for inflammasome activation in macrophages.
abstract: Pathogen-activated and damage-associated molecular patterns activate the inflammasome in macrophages. We report that mouse macrophages release IL-1β while co-incubated with pro-B (Ba/F3) cells dying, as a result of IL-3 withdrawal, by apoptosis with autophagy, but not when they are co-incubated with living, apoptotic, necrotic or necrostatin-1 treated cells. NALP3-deficient macrophages display reduced IL-1β secretion, which is also inhibited in macrophages deficient in caspase-1 or pre-treated with its inhibitor. This finding demonstrates that the inflammasome is activated during phagocytosis of dying autophagic cells. We show that activation of NALP3 depends on phagocytosis of dying cells, ATP release through pannexin-1 channels of dying autophagic cells, P(2)X(7) purinergic receptor activation, and on consequent potassium efflux. Dying autophagic Ba/F3 cells injected intraperitoneally in mice recruit neutrophils and thereby induce acute inflammation. These findings demonstrate that NALP3 performs key upstream functions in inflammasome activation in mouse macrophages engulfing dying autophagic cells, and that these functions lead to pro-inflammatory responses.
authors: Department of Biochemistry and Molecular Biology, Medical and Health Science Center, University of Debrecen, Debrecen, Hungary.
authors: Gizem
authors: G
authors: Ayna
authors: Dmitri V
authors: DV
authors: Krysko
authors: Agnieszka
authors: A
authors: Kaczmarek
authors: Goran
authors: G
authors: Petrovski
authors: Peter
authors: P
authors: Vandenabeele
authors: László
authors: L
authors: Fésüs
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects; D002352:Carrier Proteins / Q000378:metabolism; D020170:Caspase 1 / Q000378:metabolism; D002460:Cell Line; D007093:Imidazoles / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D058847:Inflammasomes / Q000378:metabolism*; D007249:Inflammation / Q000473:pathology; D007274:Injections, Intraperitoneal; D053583:Interleukin-1beta / Q000378:metabolism; D007377:Interleukin-3 / Q000172:deficiency; D015850:Interleukin-6 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D009336:Necrosis; D020556:Neutrophil Infiltration / Q000187:drug effects; D010529:Peritoneal Cavity / Q000473:pathology; D010587:Phagocytosis / Q000187:drug effects; D013864:Thioglycolates
chemical_list: D002352:Carrier Proteins; D007093:Imidazoles; D007211:Indoles; D058847:Inflammasomes; D053583:Interleukin-1beta; D007377:Interleukin-3; D015850:Interleukin-6; D008070:Lipopolysaccharides; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D013864:Thioglycolates; C507699:necrostatin-1; C017487:2-mercaptoacetate; D000255:Adenosine Triphosphate; D020170:Caspase 1