Format

Send to

Choose Destination
Cell Rep. 2018 Oct 23;25(4):921-933.e5. doi: 10.1016/j.celrep.2018.09.001.

IFNα Impairs Autophagic Degradation of mtDNA Promoting Autoreactivity of SLE Monocytes in a STING-Dependent Fashion.

Author information

1
Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology, Heraklion, Greece; Laboratory of Autoimmunity and Inflammation, Faculty of Medicine, University of Crete, Heraklion, Greece. Electronic address: kgirtzimanaki@gmail.com.
2
Laboratory of Autoimmunity and Inflammation, Faculty of Medicine, University of Crete, Heraklion, Greece.
3
Biomedical Research Foundation of the Academy of Athens, Athens, Greece.
4
Laboratory of Autoimmunity and Inflammation, Faculty of Medicine, University of Crete, Heraklion, Greece; Department of Rheumatology, University Hospital of Heraklion, Faculty of Medicine, University of Crete, Heraklion, Greece.
5
Department of Obstetrics and Gynecology, Medical School, University of Crete, Heraklion, Greece.
6
4th Department of Medicine, Attikon University Hospital, National and Kapodistrian University, Athens, Greece and Medical School, University of Cyprus, Nikosia, Cyprus; Laboratory of Immune Regulation and Tolerance, Autoimmunity and Inflammation, Biomedical Research Foundation of the Academy of Athens, Athens, Greece.
7
Laboratory of Immune Regulation and Tolerance, Autoimmunity and Inflammation, Biomedical Research Foundation of the Academy of Athens, Athens, Greece. Electronic address: pverginis@bioacademy.gr.

Abstract

Interferon α (IFNα) is a prompt and efficient orchestrator of host defense against nucleic acids but upon chronicity becomes a potent mediator of autoimmunity. Sustained IFNα signaling is linked to pathogenesis of systemic lupus erythematosus (SLE), an incurable autoimmune disease characterized by aberrant self-DNA sensing that culminates in anti-DNA autoantibody-mediated pathology. IFNα instructs monocytes differentiation into autoinflammatory dendritic cells (DCs) than potentiates the survival and expansion of autoreactive lymphocytes, but the molecular mechanism bridging sterile IFNα-danger alarm with adaptive response against self-DNA remains elusive. Herein, we demonstrate IFNα-mediated deregulation of mitochondrial metabolism and impairment of autophagic degradation, leading to cytosolic accumulation of mtDNA that is sensed via stimulator of interferon genes (STING) to promote induction of autoinflammatory DCs. Identification of mtDNA as a cell-autonomous enhancer of IFNα signaling underlines the significance of efficient mitochondrial recycling in the maintenance of peripheral tolerance. Antioxidant treatment and metabolic rescue of autolysosomal degradation emerge as drug targets in SLE and other IFNα-related pathologies.

KEYWORDS:

SLE; autoimmunity; lysosome; metabolism

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center