Interferon gamma signaling drives cardiac metabolic rewiring

  1. Ebram Tharwat Melika
  2. DiyaaElDin Ashour
  3. Kyoungmin Kim
  4. Alexander Nickel
  5. Paula Arias-Loza
  6. Xinyu Chen
  7. Panagiota Arampatzi
  8. Mugdha Srivastava
  9. Martin Väth
  10. Edécio Cunha
  11. Michaela Kuhn
  12. Georg Gasteiger
  13. Ulrich Hofmann
  14. Takahiro Higuchi
  15. Christoph Maack
  16. Stefan Frantz
  17. Anja Karlstaedt
  18. Gustavo Campos Ramos
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Abstract

Background

IFN-gamma (IFN-γ) signaling influences myocardial inflammation and fibrosis across a wide range of conditions, including ischemic and non-ischemic heart failure (HF). However, the direct effects of IFN-γ on cardiomyocytes remain poorly understood. Here, we developed a novel in vivo model to investigate how IFN-γ impacts myocardial metabolism and function.

Methods

Male C57BL/6J mice were injected intravenously with hepatotropic adeno-associated virus (AAV2/8) carrying Ifng and nLuc reporter under the albumin promoter (AAV- Ifng) or empty vector control virus (AAV-ctrl). Cardiac alterations were monitored on day 28 through flow cytometry, bulk RNA sequencing, targeted metabolomics, isolated mitochondrial activity, echocardiography, and in vivo imaging using [18F]fluordeoxyglucose ([18F]FDG) and [18F]fluoro-6-thia-heptadecanoic acid. Additionally, mice lacking IFN-γ receptor expression in cardiomyocytes (Myh6 Cre Ifngr1 fl/fl) were used to further dissect the cell-intrinsic roles of IFN-γ signaling in cardiomyocyte metabolic reprograming.

Results

After confirming liver-specific viral transfection and elevated serum IFN-γ production at physiological levels, we observed cardiac metabolic adaptation and rewiring in animals treated with AAV-Ifng compared to control animals. Myocardial bulk RNA sequencing and gene set enrichment analysis identified an IFN-γ response signature accompanied by marked down-regulations of oxidative phosphorylation and fatty acid oxidation pathways. Functional assessment of isolated cardiac mitochondria showed decreased oxygen consumption, and targeted metabolomics confirmed metabolic shifts toward glycolysis in mice overexpressing IFN-γ. In vivo imaging confirmed increased cardiac glucose uptake following AAV-Ifng treatment. Notably, these metabolic alterations were abrogated in mice with cardiomyocyte-specific deletion of IFN-γ receptors (IFNGR).

Conclusions

Systemic IFN-γ induces pronounced metabolic reprogramming in the heart, characterized by increased glucose uptake and reduced oxidative phosphorylation, via direct signaling through cardiomyocyte IFNGR. These alterations mirror those observed in aging and some forms of HF, thereby highlighting that, beyond classical inflammation, this cytokine regulates cardiac metabolism.

Novelty and significance

What is known?

  • Immunological mechanisms can impact myocardial disease progression through complex context-dependent mechanisms.

  • IFN-γ, a cytokine primarily secreted by natural killer and T cells, promotes myocardial inflammation and fibrosis in the context of autoimmune myocarditis, pressure-overload-induced heart failure, and Chagas cardiomyopathy.

  • Cytokines exert pleiotropic effects and can influence inflammatory responses through mechanisms involving control of energy metabolism.

What new information does this article contribute?

  • A novel adeno-associated virus model of systemic IFN-γ elevation allows assessment of cardio-immune-metabolic crosstalk without confounding factors.

  • IFN-γ drives cardiac metabolic reprogramming in inflammatory contexts, characterized by enhanced glucose uptake and glycolysis with mitochondrial dysfunction, ultimately altering cardiac metabolic fluxes and function.

  • The IFN-γ-induced cardiac metabolic reprogramming is, at least in part, mediated through direct signaling via receptors on cardiomyocytes.

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