Mitochondrial instability contributes to IFN-driven heart disease
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Aims
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 IFNa exposure on cardiac and cardiomyocyte function in order to better understand IFN-driven cardiac disease from the perspective of SLE.
Methods and Results
Administration of the TLR7/8 agonist, resiquimod, to C57BL6 mice, drove chronic IFN induction and reduced ejection fraction and fractional shortening compared to mice treated with vehicle control. Multiomic analysis demonstrated increased IFN signature in resiquimod treated hearts (transcriptomic and proteomic) and a decrease in genes and proteins representing electron transport chain (ETC) and cytochrome complex assembly. Integration of metabolomics with transcriptomics revealed pathways representing chemokine signaling, Toll-like receptor signaling, HIF-1 signaling and Dilated cardiomyopathy. As our in vivo model of IFN-driven SLE-like heart disease showed both proteomic and transcriptomic changes that reflected changes in mitochondrial and potentially cardiac function, we conducted an in vitro analysis of the effects of acute and chronic IFN on cardiomyocytes, the most energetically demanding cell type in the heart, and the cells most susceptible to stress and inflammation. As with our in vivo findings, proteomic and transcriptomic analysis of AC16 cardiomyocytes exposed to chronic IFNα indicated perturbation of mitochondrial pathways. Extracellular flux analysis of chronically exposed AC16 cells showed impaired basal respiration, maximal respiration, ATP production and non-glycolytic acidification, glycolysis and glycolytic capacity, indicating increased mitochondrial stress in response to chronic exposure to IFNa. MitoTracker green staining showed increased fragmentation and perinuclear localization in AC16 chronically exposed to IFN and an increase in mtDNA release and expression of proteins known to contribute to mtDNA release and detection.
Conclusions
Our results directly support a role for chronic IFN in driving cardiac dysfunction in both a mouse model of IFN-driven disease that mimics SLE and in cardiomyocytes, though enhanced mitochondrial stress, mtDNA release and potentially exacerbation of cGAS-STING-IFN axis.
Translational Perspectives
Many immune features of SLE such as elevated type I interferons, chronic inflammation, and persistent autoantibody production are strongly correlated with increased cardiovascular risk, but it remains difficult to prove direct biological causation. This study demonstrates that chronic IFN exposure induces mitochondrial dysfunction and mtDNA release in cardiomyocytes, directly complementing an in vivo model of SLE-cardiac disease. It suggests that targeting IFNs may reduce CVD risk in IFN-driven autoimmunity.
