| Title | Erythroid mitochondrial retention triggers myeloid-dependent type I interferon in human SLE. |
| Publication Type | Journal Article |
| Year of Publication | 2021 |
| Authors | Caielli S, Cardenas J, de Jesus AAlmeida, Baisch J, Walters L, Blanck JPhilippe, 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 |
| Date Published | 2021 Aug 03 |
| ISSN | 1097-4172 |
| 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. |
| DOI | 10.1016/j.cell.2021.07.021 |
| Custom 1 | |
| Alternate Journal | Cell |
| PubMed ID | 34384544 |