%0 Journal Article
%T Erythroid mitochondrial retention triggers myeloid-dependent type I interferon in human SLE.
%A Caielli S
%A Cardenas J
%A de Jesus AA
%A Baisch J
%A Walters L
%A Blanck JP
%A Balasubramanian P
%A Stagnar C
%A Ohouo M
%A Hong S
%A Nassi L
%A Stewart K
%A Fuller J
%A Gu J
%A Banchereau JF
%A Wright T
%A Goldbach-Mansky R
%A Pascual V
%J Cell
%V 184
%N 17
%D 08 2021 19
%M 34384544
%F 66.85
%R 10.1016/j.cell.2021.07.021
%X 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.