Biomedical Research Foundation Academy Of AthensAcademy Of Athens
Research Highlights :IFNα Impairs Autophagic Degradation of mtDNA Promoting Autoreactivity of SLE Monocytes in a STING-Dependent Fashion

Panayotis Verginis, Dimitrios Boumpas and colleagues published a new study in Cell Reports.

Systemic lupus erythematosus (SLE) is an autoimmune disease that causes inflammation in several organs including joints, skin, kidneys, heart and brain.  A cardinal feature of SLE is the production of interferon a (IFN-a) –a key cytokine for the antiviral response, especially in patients of active severe disease. The IFNα produced instructs monocytes differentiation into autoinflammatory dendritic cells (DCs) that potentiates the survival and expansion of autoreactive lymphocytes; however the mechanism for this effect is not known. In this paper, we demonstrate for the first time that once produced, IFNa leads to amplification and perpetuation of the aberrant immune response by interfering with the normal clearance of mitochondrial DNA.  More specifically, we found that IFNa impairs the clearance of damaged mitochondria in monocytes through de-regulation of the mitophagic pathway. This leads to accumulation of mitochondrial DNA (mtDNA) within the cytoplasm where it is recognized by specialized receptors (such as the stimulator of interferon genes STING) and potently activates monocytes.

Activation of monocytes by mtDNA leads to secretion of pro-inflammatory cytokines and enhances their immunogenicity and promotes pathogenic autoimmunity by overriding homeostatic mechanisms. These data reveal an unappreciated role of IFNa in SLE pathogenesis proposing new mechanisms that could be explored therapeutically. Antioxidant treatment and metabolic rescue of autolysosomal degradation represent potential drug targets in SLE and other IFNα-related pathologies.

 



Pubmed

Gkirtzimanaki K, Kabrani E, Nikoleri D, Polyzos A, Blanas A, Sidiropoulos P, Makrigiannakis A, Bertsias G, Boumpas DT, Verginis P.
IFNα Impairs Autophagic Degradation of mtDNA Promoting Autoreactivity of SLE Monocytes in a STING-Dependent Fashion
Cell Rep. 2018 Oct 23;25(4):921-933.e5. doi: 10.1016/j.celrep.2018.09.001