{Reference Type}: Journal Article
{Title}: Erythroid mitochondrial retention triggers myeloid-dependent type I interferon in human SLE.
{Author}: Caielli S;Cardenas J;de Jesus AA;Baisch J;Walters L;Blanck JP;Balasubramanian P;Stagnar C;Ohouo M;Hong S;Nassi L;Stewart K;Fuller J;Gu J;Banchereau JF;Wright T;Goldbach-Mansky R;Pascual V;
{Journal}: Cell
{Volume}: 184
{Issue}: 17
{Year}: 08 2021 19
{Factor}: 66.85
{DOI}: 10.1016/j.cell.2021.07.021
{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.