TY - JOUR
T1 - Erythroid mitochondrial retention triggers myeloid-dependent type I interferon in human SLE
AU - Caielli, Simone
AU - Cardenas, Jacob
AU - de Jesus, Adriana Almeida
AU - Baisch, Jeanine
AU - Walters, Lynnette
AU - Blanck, Jean Philippe
AU - Balasubramanian, Preetha
AU - Stagnar, Cristy
AU - Ohouo, Marina
AU - Hong, Seunghee
AU - Nassi, Lorien
AU - Stewart, Katie
AU - Fuller, Julie
AU - Gu, Jinghua
AU - Banchereau, Jacques F.
AU - Wright, Tracey
AU - Goldbach-Mansky, Raphaela
AU - Pascual, Virginia
N1 - Publisher Copyright:
© 2021 Elsevier Inc.
PY - 2021/8/19
Y1 - 2021/8/19
N2 - 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.
AB - 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.
KW - CANDLE syndrome
KW - HIF2a
KW - autoimmunity
KW - cGAS
KW - human erythropoiesis
KW - interferon
KW - mitochondrial DNA
KW - mitophagy
KW - proteasome
KW - systemic lupus erythematosus
UR - http://www.scopus.com/inward/record.url?scp=85112750696&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85112750696&partnerID=8YFLogxK
U2 - 10.1016/j.cell.2021.07.021
DO - 10.1016/j.cell.2021.07.021
M3 - Article
C2 - 34384544
AN - SCOPUS:85112750696
SN - 0092-8674
VL - 184
SP - 4464-4479.e19
JO - Cell
JF - Cell
IS - 17
ER -