Erythroid mitochondrial retention triggers myeloid-dependent type I interferon in human SLE.
Cell
; 184(17): 4464-4479.e19, 2021 08 19.
Article
em En
| MEDLINE
| ID: mdl-34384544
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.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Interferon Tipo I
/
Células Mieloides
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Lúpus Eritematoso Sistêmico
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Mitocôndrias
Limite:
Adolescent
/
Child
/
Child, preschool
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Humans
Idioma:
En
Revista:
Cell
Ano de publicação:
2021
Tipo de documento:
Article