title: Defects in mitochondrial clearance predispose human monocytes to interleukin-1β hypersecretion.
abstract: Most hereditary periodic fever syndromes are mediated by deregulated IL-1β secretion. The generation of mature IL-1β requires two signals: one that induces synthesis of inflammasome components and substrates and a second that activates inflammasomes. The mechanisms that mediate autoinflammation in mevalonate kinase deficiency, a periodic fever disease characterized by a block in isoprenoid biosynthesis, are poorly understood. In studying the effects of isoprenoid shortage on IL-1 β generation, we identified a new inflammasome activation signal that originates from defects in autophagy. We find that hypersecretion of IL-1β and IL-18 requires reactive oxygen species and is associated with an oxidized redox status of monocytes but not lymphocytes. IL-1β hypersecretion by monocytes involves decreased mitochondrial stability, release of mitochondrial content into the cytosol and attenuated autophagosomal degradation. Defective autophagy, as established by ATG7 knockdown, results in prolonged cytosolic retention of damaged mitochondria and increased IL-1β secretion. Finally, activation of autophagy in healthy but not mevalonate kinase deficiency patient cells reduces IL-1β secretion. Together, these results indicate that defective autophagy can prime monocytes for mitochondria-mediated NLRP3 inflammasome activation, thereby contributing to hypersecretion of IL-1β in mevalonate kinase deficiency.
authors.affiliation: From the Department of Pediatric Immunology and Infectious Diseases, University Medical Center Utrecht, Wilhelmina Children's Hospital, 3584 EA Utrecht, The Netherlands.
authors.forename: Robert
authors.initials: R
authors.lastname: van der Burgh
authors.forename: Lotte
authors.initials: L
authors.lastname: Nijhuis
authors.forename: Kalliopi
authors.initials: K
authors.lastname: Pervolaraki
authors.forename: Ewoud B
authors.initials: EB
authors.lastname: Compeer
authors.forename: Lieneke H
authors.initials: LH
authors.lastname: Jongeneel
authors.forename: Marielle
authors.initials: M
authors.lastname: van Gijn
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Coffer
authors.forename: Michael P
authors.initials: MP
authors.lastname: Murphy
authors.forename: Pier G
authors.initials: PG
authors.lastname: Mastroberardino
authors.forename: Joost
authors.initials: J
authors.lastname: Frenkel
authors.forename: Marianne
authors.initials: M
authors.lastname: Boes
mesh_terms: D000293:Adolescent; D001343:Autophagy; D002460:Cell Line; D002648:Child; D002675:Child, Preschool; D003600:Cytosol / Q000378:metabolism; D004272:DNA, Mitochondrial / Q000378:metabolism; D004198:Disease Susceptibility / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D058847:Inflammasomes / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism*; D053078:Membrane Potential, Mitochondrial; D054078:Mevalonate Kinase Deficiency / Q000378:metabolism / Q000473:pathology; D008928:Mitochondria / Q000378:metabolism*; D008954:Models, Biological; D009000:Monocytes / Q000378:metabolism* / Q000473:pathology*; D010084:Oxidation-Reduction; D013729:Terpenes / Q000378:metabolism
chemical_list: D004272:DNA, Mitochondrial; C508585:IL1B protein, human; D058847:Inflammasomes; D053583:Interleukin-1beta; D013729:Terpenes
keywords: Autoinflammatory Disorder; Autophagy; Interleukin; Mitochondrial DNA; Monocytes; Periodic Fever; Redox Regulation