Mitochondrial instability contributes to IFN-driven heart disease

Type I interferons (IFNs) are linked to an increased risk of cardiovascular disease and are chronically elevated in systemic autoimmune diseases such as systemic lupus erythematosus (SLE). We evaluated the effect of chronic IFNα exposure on heart function using the resiquimod model of IFN-inducible SLE. Echocardiography showed that C57BL/6 mice had reduced left ventricular function following administration of resiquimod (R848) for 4 weeks. This was accompanied by increased α-SMA deposition, infiltration of both innate and adaptive immune cells and a robust increase in fibroblasts. Importantly endothelial cell abundance decreased, as measured by CD31 staining. Transcriptomic and proteomic analysis showed a concordant increase in pathways representing type I IFN response, ischemia, oxidative stress, fibrosis and cardiomyocyte stress, whereas genes and proteins representing oxidative phosphorylation were decreased, as were metabolites on the TCA cycle, suggesting impaired ATP production in the R848-treated hearts. As cardiomyocytes are the most energetically demanding cell type in the heart, and the cells most susceptible to stress and inflammation, we assessed the effects of chronic IFN exposure on their function. Chronically exposed AC16 cells showed impaired basal respiration, increased mitochondrial depolarization, increased mitochondrial mass and fragmentation, suggesting mitochondrial stress. mtDNA release is a key consequence of mitochondrial stress, driving cGAS activation and induction of IFN-stimulated genes. Not only was enhanced mtDNA detectable in chronically activated AC16s, but the increased expression of ISGs could be inhibited by the cGAS inhibitor G140. Thus chronic IFN exposure promotes cardiomyocyte stress, mitochondrial DNA release and a feed forward inflammatory loop driven by cGAS, a recently identified mediator of cardiovascular disease. Importantly, human iPSC-derived cardiomyocytes recapitulated our key findings in AC16 cells, and cGAS inhibition could rescue ISG expression and mitochondrial depolarization.