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Suppression of Pro-fibrotic Signaling Potentiates Factor-mediated Reprogramming of Mouse Embryonic Fibroblasts into Induced Cardiomyocytes
Published on: June 3, 2018
Cancer-driven cytokine immunomodulation ameliorates cardiac function and suppresses fibrosis
Laris Achlaug1, Lama Awwad1, Irina Langier Goncalves1
1Department of Cell Biology and Cancer Science, Israel.
Abstract:
Heart failure remains a leading cause of morbidity and mortality worldwide, with limited progress in the development of novel therapies. It has been demonstrated that tumor growth improves cardiac function and reduces myocardial fibrosis in mouse models of heart failure. It is clear that cancer cell implantation is not a possible therapeutic strategy for heart failure. Therefore, we further studied the underlying mechanism involved, with the objective of demonstrating its broad therapeutic applicability. We show that a single intravenous injection of serum from tumor-bearing mice rapidly augments left-ventricular fractional shortening and suppresses fibrosis in the heart, diaphragm, and skeletal muscles. Cytokine profiling identified IFNγ and TNFα as essential mediators secreted downstream of natural killer (NK) cell activation. Purified recombinant IFNγ and TNFα mimic the serum effect, polarizing cardiac and skeletal macrophages toward an anti-inflammatory, reparative state. We further show that macrophage depletion abrogates the observed beneficial effect, confirming their critical role. Our findings define a novel NK cell-macrophage cytokine axis that reverses cardiac dysfunction and fibrosis in pressure-overload (transverse aortic constriction) and ATF3-transgenic heart failure models. Together, these findings define a novel host-tumor microenvironment response through cytokine secretion, which leads to cardiac repair and dissolution of fibrosis. This work presents a novel therapeutic strategy for harnessing innate immune cells in the treatment of heart failure and fibrotic disease.
Insights
Serum from tumor-bearing mice rapidly improves heart function and reduces fibrosis by activating natural killer (NK) cells. This NK cell-macrophage cytokine axis offers a novel therapeutic strategy for heart failure and fibrotic diseases.
Area of Science:
- Immunology
- Cardiovascular Biology
- Oncology
Background:
- Heart failure is a major global health challenge with limited therapeutic options.
- Tumor growth has been observed to improve cardiac function and reduce fibrosis in heart failure models.
- The underlying mechanisms of this host-tumor interaction require elucidation for therapeutic application.
Purpose of the Study:
- To investigate the therapeutic potential of serum from tumor-bearing mice in heart failure.
- To identify the key molecular mediators and cellular pathways involved in tumor-induced cardiac repair.
- To establish a novel therapeutic strategy for heart failure and fibrotic conditions.
Main Methods:
- Administration of serum from tumor-bearing mice to mouse models of heart failure.
- Assessment of cardiac function (left-ventricular fractional shortening) and fibrosis.
- Cytokine profiling to identify key mediators (IFNγ, TNFα).
- Investigation of the role of natural killer (NK) cells and macrophages via depletion studies.
Main Results:
- Serum injection significantly improved cardiac function and reduced fibrosis in multiple organs.
- Interferon-gamma (IFNγ) and Tumor Necrosis Factor-alpha (TNFα) were identified as essential mediators.
- Recombinant IFNγ and TNFα mimicked the serum's beneficial effects.
- Macrophages were shown to be critical for the therapeutic response, polarized to an anti-inflammatory state.
Conclusions:
- A novel NK cell-macrophage cytokine axis drives cardiac repair and fibrosis resolution.
- This axis, activated by tumor-derived factors, represents a promising therapeutic avenue for heart failure.
- Harnessing innate immunity offers a new strategy for treating heart failure and fibrotic diseases.
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