Erythroid mitochondrial retention triggers myeloid-dependent type I interferon in human SLE.
Cell
; 184(17): 4464-4479.e19, 2021 08 19.
Article
in 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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Interferon Type I
/
Myeloid Cells
/
Lupus Erythematosus, Systemic
/
Mitochondria
Limits:
Adolescent
/
Child
/
Child, preschool
/
Humans
Language:
En
Journal:
Cell
Year:
2021
Type:
Article