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

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.
Competing Interests: Declaration of interests V.P. has received consulting honoraria from Sanofi, Astra Zeneca, and Moderna and is the recipient of a research grant from Sanofi and a contract from Astra Zeneca. J.F.B. is a member of the S.A.B. of Neovacs.
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