Erythroid mitochondrial retention triggers myeloid-dependent type I interferon in human SLE

Simone Caielli, Jacob Cardenas, Adriana Almeida de Jesus, Jeanine Baisch, Lynnette Walters, Jean Philippe Blanck, Preetha Balasubramanian, Cristy Stagnar, Marina Ohouo, Seunghee Hong, Lorien Nassi, Katie Stewart, Julie Fuller, Jinghua Gu, Jacques F. Banchereau, Tracey Wright, Raphaela Goldbach-Mansky, Virginia Pascual

Research output: Contribution to journalArticlepeer-review

44 Scopus citations


Emerging evidence supports that mitochondrial dysfunction contributes to systemic lupus erythematosus (SLE) pathogenesis. Here we show that programmed mitochondrial removal, a hallmark of mammalian erythropoiesis, is defective in SLE. Specifically, we demonstrate that during human erythroid cell maturation, a hypoxia-inducible factor (HIF)-mediated metabolic switch is responsible for the activation of the ubiquitin-proteasome system (UPS), which precedes and is necessary for the autophagic removal of mitochondria. A defect in this pathway leads to accumulation of red blood cells (RBCs) carrying mitochondria (Mito+ RBCs) in SLE patients and in correlation with disease activity. Antibody-mediated internalization of Mito+ RBCs induces type I interferon (IFN) production through activation of cGAS in macrophages. Accordingly, SLE patients carrying both Mito+ RBCs and opsonizing antibodies display the highest levels of blood IFN-stimulated gene (ISG) signatures, a distinctive feature of SLE.

Original languageEnglish (US)
Pages (from-to)4464-4479.e19
Issue number17
StatePublished - Aug 19 2021


  • CANDLE syndrome
  • HIF2a
  • autoimmunity
  • cGAS
  • human erythropoiesis
  • interferon
  • mitochondrial DNA
  • mitophagy
  • proteasome
  • systemic lupus erythematosus

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)


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