Oxidized mitochondrial nucleoids released by neutrophils drive type I interferon production in human lupus

Simone Caielli, Shruti Athale, Bojana Domic, Elise Murat, Manjari Chandra, Romain Banchereau, Jeanine Baisch, Kate Phelps, Sandra Clayton, Mei Gong, Tracey Wright, Marilynn Punaro, Karolina Palucka, Cristiana Guiducci, Jacques Banchereau, Virginia Pascual

Research output: Contribution to journalArticle

147 Scopus citations

Abstract

Autoantibodies against nucleic acids and excessive type I interferon (IFN) are hallmarks of human systemic lupus erythematosus (SLE). We previously reported that SLE neutrophils exposed to TLR7 agonist autoantibodies release interferogenic DNA, which we now demonstrate to be of mitochondrial origin. We further show that healthy human neutrophils do not complete mitophagy upon induction of mitochondrial damage. Rather, they extrude mitochondrial components, including DNA (mtDNA), devoid of oxidized (Ox) residues. When mtDNA undergoes oxidation, it is directly routed to lysosomes for degradation. This rerouting requires dissociation from the transcription factor A mitochondria (TFAM), a dual high-mobility group (HMG) protein involved in maintenance and compaction of the mitochondrial genome into nucleoids. Exposure of SLE neutrophils, or healthy IFN-primed neutrophils, to antiribonucleotide protein autoantibodies blocks TFAM phosphorylation, a necessary step for nucleoid dissociation. Consequently, Ox nucleoids accumulate within mitochondria and are eventually extruded as potent interferogenic complexes. In support of the in vivo relevance of this phenomenon, mitochondrial retention of Ox nucleoids is a feature of SLE blood neutrophils, and autoantibodies against Ox mtDNA are present in a fraction of patients. This pathway represents a novel therapeutic target in human SLE.

Original languageEnglish (US)
Pages (from-to)697-713
Number of pages17
JournalJournal of Experimental Medicine
Volume213
Issue number5
DOIs
StatePublished - May 2 2016

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Caielli, S., Athale, S., Domic, B., Murat, E., Chandra, M., Banchereau, R., Baisch, J., Phelps, K., Clayton, S., Gong, M., Wright, T., Punaro, M., Palucka, K., Guiducci, C., Banchereau, J., & Pascual, V. (2016). Oxidized mitochondrial nucleoids released by neutrophils drive type I interferon production in human lupus. Journal of Experimental Medicine, 213(5), 697-713. https://doi.org/10.1084/jem.20151876