Oxidized mitochondrial nucleoids released by neutrophils drive type I interferon production in human lupus. Academic Article uri icon

Overview

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.

authors

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

publication date

  • April 18, 2016

Research

keywords

  • DNA, Mitochondrial
  • Interferon Type I
  • Lupus Erythematosus, Systemic
  • Mitochondria
  • Neutrophils

Identity

PubMed Central ID

  • PMC4854735

Scopus Document Identifier

  • 84969263240

Digital Object Identifier (DOI)

  • 10.1038/nature08780

PubMed ID

  • 27091841

Additional Document Info

volume

  • 213

issue

  • 5