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

Simone Caielli, Jacob Cardenas, Adriana Almeida de Jesus, Jeanine Baisch, Lynnette Walters, Jean Philippe Blanck, Preetha Balasubramanian, Cristy Stagnar, Marina Ohouo, Seunghee Hong, Lorien Nassi, Katie Stewart, Julie Fuller, Jinghua Gu, Jacques F. Banchereau, Tracey Wright, Raphaela Goldbach-Mansky, Virginia Pascual

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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.

Original languageEnglish
Pages (from-to)4464-4479.e19
JournalCell
Volume184
Issue number17
DOIs
Publication statusPublished - 2021 Aug 19

Bibliographical note

Funding Information:
We are grateful to our SLE and JDM patients, their families, the healthy individuals who participated in our study, and the members of the Pediatric Rheumatology Clinics at Texas Scottish Rite Hospital for Children and the Children's Medical Center in Dallas, TX, USA. We thank Dr. A. Darehshouri (UTSW medical center: Dallas) and Dr. L. Cohen-Gould (WCMC: New York) for help with transmission electron microscopy (TEM) studies, and the Genomics Core at the Baylor Scott and White Research Institute (Dallas, TX, YSA) for RNA sequencing. This work was supported by grants from NIAMS (CORT P50AR070594 Center for Lupus Research to V.P. and J.F.B.), NIAID, NIH (U19 AI082715 to V.P.), Lupus Innovation Award (Lupus Research Alliance, to S.C.) and funds from the Drukier Institute for Children's Health at Weill Cornell Medicine. S.C. P.B. C.S. and M.O. performed the experiments. A.A.d.J. J.B. L.W. L.N. K.S. J.F. and T.W. coordinated the collection of human samples. J.P.B. assisted in flow cytometry analysis. J.C. and J.G. analyzed RNA-seq data and provided recommendations for all statistical analysis. S.C. and V.P. conceptualized the study, designed experiments, interpreted data, and wrote the manuscript. J.F.B. R.G.-M. and V.P. supervised the study. 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.

Funding Information:
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.

Funding Information:
We are grateful to our SLE and JDM patients, their families, the healthy individuals who participated in our study, and the members of the Pediatric Rheumatology Clinics at Texas Scottish Rite Hospital for Children and the Children’s Medical Center in Dallas, TX, USA. We thank Dr. A. Darehshouri (UTSW medical center: Dallas) and Dr. L. Cohen-Gould (WCMC: New York) for help with transmission electron microscopy (TEM) studies, and the Genomics Core at the Baylor Scott and White Research Institute (Dallas, TX, YSA) for RNA sequencing. This work was supported by grants from NIAMS ( CORT P50AR070594 Center for Lupus Research to V.P. and J.F.B.), NIAID , NIH ( U19 AI082715 to V.P.), Lupus Innovation Award (Lupus Research Alliance, to S.C.) and funds from the Drukier Institute for Children’s Health at Weill Cornell Medicine .

Publisher Copyright:
© 2021 Elsevier Inc.

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)

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