1. 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, and Pascual V
- Subjects
- Adolescent, Basic Helix-Loop-Helix Transcription Factors metabolism, Child, Child, Preschool, Erythroblasts metabolism, Erythroblasts ultrastructure, Erythrocytes metabolism, Erythropoiesis, Humans, Mitophagy, Proteasome Endopeptidase Complex metabolism, Ubiquitin metabolism, Interferon Type I metabolism, Lupus Erythematosus, Systemic metabolism, Mitochondria metabolism, Myeloid Cells metabolism
- 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., 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., (Copyright © 2021 Elsevier Inc. All rights reserved.)- Published
- 2021
- Full Text
- View/download PDF