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

Summary

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.

Graphical Abstract

Highlights

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  IFNα obstructs autophagic flux in SLE monocytes through lysosomal alkalinization

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  IFNα signaling induces oxidative stress that affects lysosomal pH through mTOR

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  Impaired clearance of damaged mitochondria leads to cytosolic mtDNA accumulation

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  Autophagic escape of mtDNA is sensed by STING and primes monocytes autoimmunity

Abstract

In lupus, sustained IFNα signaling leads to anti-DNA autoimmunity. Gkirtzimanaki et al. propose that excessive IFNα damages mitochondrial respiration, leading to oxidative stress that impairs lysosomal degradation and obstructs autophagic clearance. Undegraded mtDNA escapes in the cytoplasm and is sensed, priming monocytes cell-autonomously to initiate an anti-viral-like response against self-DNA.