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

K. Gkirtzimanaki, E. Kabrani, D. Nikoleri, A. Polyzos, A Blanas, P. Sidiropoulos, A. Makrigiannakis, G. Bertsias, D. Boumpas, P. Verginis

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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.
Original languageEnglish
Pages (from-to)921-933.e5
JournalCell Reports
Volume25
Issue number4
DOIs
Publication statusPublished - 23 Oct 2018

Cite this

Gkirtzimanaki, K., Kabrani, E., Nikoleri, D., Polyzos, A., Blanas, A., Sidiropoulos, P., ... Verginis, P. (2018). IFNα Impairs Autophagic Degradation of mtDNA Promoting Autoreactivity of SLE Monocytes in a STING-Dependent Fashion. Cell Reports, 25(4), 921-933.e5. https://doi.org/10.1016/j.celrep.2018.09.001