title: Autophagy controls IL-1beta secretion by targeting pro-IL-1beta for degradation.
abstract: Autophagy is a key regulator of cellular homeostasis that can be activated by pathogen-associated molecules and recently has been shown to influence IL-1β secretion by macrophages. However, the mechanisms behind this are unclear. Here, we describe a novel role for autophagy in regulating the production of IL-1β in antigen-presenting cells. After treatment of macrophages with Toll-like receptor ligands, pro-IL-1β was specifically sequestered into autophagosomes, whereas further activation of autophagy with rapamycin induced the degradation of pro-IL-1β and blocked secretion of the mature cytokine. Inhibition of autophagy promoted the processing and secretion of IL-1β by antigen-presenting cells in an NLRP3- and TRIF-dependent manner. This effect was reduced by inhibition of reactive oxygen species but was independent of NOX2. Induction of autophagy in mice in vivo with rapamycin reduced serum levels of IL-1β in response to challenge with LPS. These data demonstrate that autophagy controls the production of IL-1β through at least two separate mechanisms: by targeting pro-IL-1β for lysosomal degradation and by regulating activation of the NLRP3 inflammasome.
authors.affiliation: Adjuvant Research Group, School of Biochemistry and Immunology, Trinity College Dublin, College Green, Dublin 2, Ireland. jaharris@tcd.ie
authors.forename: James
authors.initials: J
authors.lastname: Harris
authors.forename: Michelle
authors.initials: M
authors.lastname: Hartman
authors.forename: Caitrionna
authors.initials: C
authors.lastname: Roche
authors.forename: Shijuan G
authors.initials: SG
authors.lastname: Zeng
authors.forename: Amy
authors.initials: A
authors.lastname: O'Shea
authors.forename: Fiona A
authors.initials: FA
authors.lastname: Sharp
authors.forename: Eimear M
authors.initials: EM
authors.lastname: Lambe
authors.forename: Emma M
authors.initials: EM
authors.lastname: Creagh
authors.forename: Douglas T
authors.initials: DT
authors.lastname: Golenbock
authors.forename: Jurg
authors.initials: J
authors.lastname: Tschopp
authors.forename: Hardy
authors.initials: H
authors.lastname: Kornfeld
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Fitzgerald
authors.forename: Ed C
authors.initials: EC
authors.lastname: Lavelle
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D000938:Antigen-Presenting Cells / Q000166:cytology / Q000378:metabolism*; D001343:Autophagy / Q000187:drug effects / Q000502:physiology*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D005260:Female; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism*; D008024:Ligands; D008070:Lipopolysaccharides / Q000494:pharmacology; D008247:Lysosomes / Q000235:genetics / Q000378:metabolism*; D008264:Macrophages / Q000166:cytology / Q000378:metabolism*; D008562:Membrane Glycoproteins; D051379:Mice; D008807:Mice, Inbred BALB C; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D020123:Sirolimus / Q000494:pharmacology; D051193:Toll-Like Receptors / Q000235:genetics / Q000378:metabolism
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D000900:Anti-Bacterial Agents; D002352:Carrier Proteins; D053583:Interleukin-1beta; D008024:Ligands; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D020123:Sirolimus; D051193:Toll-Like Receptors; C492716:Nlrp3 protein, mouse; C476286:Ticam1 protein, mouse; C488842:Cybb protein, mouse