Defects in mitochondrial clearance predispose human monocytes to interleukin-1β hypersecretion.

TitleDefects in mitochondrial clearance predispose human monocytes to interleukin-1β hypersecretion.
Publication TypeJournal Article
Year of Publication2014
Authorsvan der Burgh, R, Nijhuis, L, Pervolaraki, K, Compeer, EB, Jongeneel, LH, van Gijn, M, Coffer, PJ, Murphy, MP, Mastroberardino, PG, Frenkel, J, Boes, M
JournalJ Biol Chem
Volume289
Issue8
Pagination5000-12
Date Published2014 Feb 21
ISSN1083-351X
KeywordsAdolescent, Autophagy, Cell Line, Child, Child, Preschool, Cytosol, Disease Susceptibility, DNA, Mitochondrial, Humans, Inflammasomes, Interleukin-1beta, Membrane Potential, Mitochondrial, Mevalonate Kinase Deficiency, Mitochondria, Models, Biological, Monocytes, Oxidation-Reduction, Terpenes
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.

DOI10.1074/jbc.M113.536920
Alternate JournalJ. Biol. Chem.
Citation Key10.1074/jbc.M113.536920
PubMed ID24356959
PubMed Central IDPMC3931060
Grant ListMC_U105663142 / / Medical Research Council / United Kingdom