Cited by 228Systemic Lupus Erythematosus ResearchAutophagy in Disease and Therapyinterferon and immune responses

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

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Caielli, Simone, Cardenas, Jacob, de Jesus, Adriana Almeida, Baisch, Jeanine, Walters, Lynnette, Blanck, Jean Philippe, Balasubramanian, Preetha, Stagnar, Cristy +10 more·2021·Cell

Abstract

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.

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Crossref · 10.1016/j.cell.2021.07.021

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  • Abnormal retention of mitochondria in mature erythrocytes in patients with SLE is caused by a defective hypoxia-inducible factor-mediated metabolic switch that impairs activation of the ubiquitin-proteasome system necessary for mitophagy during erythroid maturation.

    “Abnormal retention of mitochondria in mature erythrocytes in patients with SLE is caused by a defective hypoxia-inducible factor (HIF)-mediated metabolic switch that leads to impaired activation of the ubiquitin-proteasome system, necessary for the execution of mitophagy during human erythroid cell maturation”

    From The role of mitochondria in rheumatic diseases (2022) · cites this paper as [119]

  • High interferon-stimulated gene signatures in patients with SLE are associated with the presence of mitochondria-containing erythrocytes and opsonizing antibodies.

    “high interferon-stimulated gene signatures in patients with SLE are associated with the presence of mitochondria-containing erythrocytes and opsonizing antibodies119”

    From The role of mitochondria in rheumatic diseases (2022) · cites this paper as [119]

  • Phagocytosis of opsonized mitochondria-containing erythrocytes induces activation of the cGAS-STING pathway in macrophages and subsequent production of type I interferons.

    “phagocytosis of opsonized mitochondria-containing erythrocytes induces activation of the DNA-sensing cyclic GMP-AMP synthase–stimulator of interferon genes (cGAS–STING) pathway in macrophages and induces subsequent production of type I interferons119”

    From The role of mitochondria in rheumatic diseases (2022) · cites this paper as [119]

  • A proportion of erythrocytes contain mitochondria in SLE, although mitochondria are normally absent in mature erythrocytes.

    “a study published in 2021 revealed that a proportion of erythrocytes contain mitochondria in SLE119”

    From The role of mitochondria in rheumatic diseases (2022) · cites this paper as [119]

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Authors
Caielli, S., Cardenas, J., de Jesus, A. A., Baisch, J., Walters, L., Blanck, J. P., Balasubramanian, P., Stagnar, C., Ohouo, M., Hong, S., Nassi, L., Stewart, K., Fuller, J., Gu, J., Banchereau, J. F., Wright, T., Goldbach-Mansky, R., & Pascual, V.
Affiliations
  • Weill Cornell Medicine (US)
  • Texas Scottish Rite Hospital for Children (US)
  • The Jackson Laboratory for Genomic Medicine (US)
Corresponding author
  • Caielli, Simone
  • Pascual, Virginia
Venue
Cell
Publisher
Elsevier BV
Published
2021-08
Volume
184
Issue
17
Pages
4464-4479.e19
ISSN
0092-8674 (ISSN-L)
OpenAlex
W3189265697
Cited by
228
References
88
Citations by year
2026: 36 · 2025: 53 · 2024: 60 · 2023: 40 · 2022: 33 · 2021: 6
FWCI
26.18
Type
journal article
Language
en
Open access
Locations
  • Cell (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • The Mouseion at the JAXlibrary (Jackson Laboratory) (submittedVersion)
Funders
  • NIH (U19 AI082715)
  • Sanofi
  • AstraZeneca
  • Weill Cornell Medical College
  • National Institute of Allergy and Infectious Diseases
  • Lupus Research Alliance
  • National Institute of Arthritis and Musculoskeletal and Skin Diseases
Topics
  • Health Sciences › Medicine › Rheumatology › Systemic Lupus Erythematosus Research
  • Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
  • Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
Keywords
systemic lupus erythematosus, erythropoiesis, autophagy, hypoxia-inducible factor, ubiquitin-proteasome system, mitochondrial dysfunction, type I interferon, cGAS, macrophages, opsonic antibodies, interferon-stimulated genes, disease activity
MeSH terms
Endothelial PAS Domain-Containing Protein 1, Adolescent, Child, Child, Preschool, Erythroblasts, Erythrocytes, Erythropoiesis, Humans, Interferon Type I, Lupus Erythematosus, Systemic, Mitochondria, Myeloid Cells, Ubiquitin, Proteasome Endopeptidase Complex, Basic Helix-Loop-Helix Transcription Factors, Basic Helix-Loop-Helix Proteins, Mitophagy

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