title: Phagocytosis of cells dying through autophagy induces inflammasome activation and IL-1β release in human macrophages.
abstract: Phagocytosis of naturally dying cells usually blocks inflammatory reactions in host cells. We have recently observed that clearance of cells dying through autophagy leads to a pro-inflammatory response in human macrophages. Investigating this response further, we found that during engulfment of MCF-7 or 293T cells undergoing autophagic death, but not apoptotic or anoikic ones, caspase-1 was activated and IL-1β was processed, then secreted in a MyD88-independent manner. Autophagic dying cells were capable of preventing some LPS-induced pro-inflammatory responses, such as TNFα, IL-6 and IL-8 induction, but synergized with LPS for IL-1β production. Caspase-1 inhibition prevented macrophage IL-1β release triggered by the dying cells and also other pro-inflammatory cytokines which were not formed in the presence of IL-1 receptor antagonist anakinra either. IL-1β secretion was also observed using calreticulin knock down or necrostatin treated autophagic MCF-7 cells and it required phagocytosis of the dying cells which led to ATP secretion from macrophages. Blocking K (+) efflux during phagocytosis, the presence of apyrase, adding an antagonist of the P2X7 receptor or silencing the NOD-like receptor protein NALP3 inhibited IL-1β secretion. These data suggest that during phagocytosis of autophagic dying cells ATP, acting through its receptor, initiates K (+) efflux, inflammasome activation and secretion of IL-1β, which initiates further pro-inflammatory events. Thus, autophagic death of malignant cells and their clearance may lead to immunogenic response.
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical and Health Science Center, University of Debrecen, Debrecen, Hungary. gokip@indi.biochem.dote.hu [corrected].
authors.forename: Goran
authors.initials: G
authors.lastname: Petrovski
authors.forename: Gizem
authors.initials: G
authors.lastname: Ayna
authors.forename: Gyöngyike
authors.initials: G
authors.lastname: Majai
authors.forename: Judit
authors.initials: J
authors.lastname: Hodrea
authors.forename: Szilvia
authors.initials: S
authors.lastname: Benko
authors.forename: András
authors.initials: A
authors.lastname: Mádi
authors.forename: László
authors.initials: L
authors.lastname: Fésüs
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects; D045744:Cell Line, Tumor; D006801:Humans; D058847:Inflammasomes / Q000378:metabolism*; D018836:Inflammation Mediators / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D058486:Receptors, Purinergic P2X7 / Q000378:metabolism
chemical_list: C508585:IL1B protein, human; D058847:Inflammasomes; D018836:Inflammation Mediators; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D053594:Myeloid Differentiation Factor 88; D058486:Receptors, Purinergic P2X7; D000255:Adenosine Triphosphate