Inflammation is crucial for healing, but excessive inflammation can exacerbate tissue damage and impair function, which is evident in myocardial infarction (MI). An inflammatory process is triggered when heart tissue is damaged, which worsens tissue destruction and can lead to heart failure. Previously, it was believed that myeloid cells, responding to signals from dying cells, were responsible for the inflammation and tissue damage in MI. However, recent findings indicate that non-immune cells also trigger an inflammatory response through the CGAS-STING pathway and type I interferon.
The CGAS-STING pathway is an innate immune response mechanism by which cells detect the presence of viral or damaged cellular DNA in the cytoplasm. The CGAS enzyme is activated upon detecting such DNA, synthesizing the molecule cGAMP. This molecule binds to the STING receptor (stimulator of interferon genes), activating immune defenses, including producing type I interferons (IFNs).
This cascade results in the activation of numerous ISGs that amplify inflammation in the heart. Since ISG expression can occur in various cell types, the general term for cells expressing ISGs is interferon-induced cells (IFNIC). Previous studies have shown that suppressing the IFN response during myocardial infarction can protect the heart from further damage. Researchers from the University of California, San Diego, hypothesized that a group of cells producing interferon is activated in the heart during MI. IFN signals reach surrounding cells, promoting the formation of IFNIC colonies and triggering inflammation.
Myocardial Infarction Triggers an Interferon Response in the Border Zone Between Healthy and Damaged Heart Tissue
Scientists analyzed heart tissue from mice and humans after myocardial infarction and found that ISG genes were activated in IFNIC cell colonies in the border zone between healthy and damaged heart tissue. These IFNIC colonies were present in normal mice but absent in mice with mutations impairing the interferon response. IFNIC colonies appeared as early as the first day after MI and persisted for up to 28 days.
As in mice, humans also exhibited IFNIC cell colonies in the border zone, confirmed by the expression of the genes MX1 and IFIT1. These colonies were absent in healthy tissues, indicating that myocardial infarction triggers an interferon response in the border zone that was previously unrecognized.
Cardiomyocytes Are the Primary Sources of Interferon in IFNIC Colonies
Researchers created mice lacking the Irf3 gene in various cell types, including cardiomyocytes, fibroblasts, macrophages, neutrophils, and endothelial cells. The Irf3 gene activates the signaling pathway that triggers type I interferon production in response to viral infections or cell damage. Removing the Irf3 gene, specifically in cardiomyocytes, disrupted the formation of IFNIC colonies in the border zone, while other cell types had little effect on this process. These results indicate that cardiomyocytes are the primary initiators of the type I interferon response, with 80% of type I IFN expression occurring in cardiomyocytes near the damage zone. However, even in mice lacking Irf3, IFNIC colonies did not wholly disappear, suggesting a role for other cells, such as border zone fibroblasts, in the process.
The Cause of IFNIC Colony Formation Is Nuclear Rupture in Border Zone Cardiomyocytes
After myocardial infarction, cardiomyocytes in the zone between healthy and damaged tissue undergo mechanical deformation. This deformation can cause nuclear envelope ruptures, allowing DNA to leak into the cytoplasm, where the CGAS enzyme recognizes it. This process triggers a cascade of reactions, including activation of the IRF3 protein and type I interferon production. IFN, in turn, stimulates nearby cells, leading to the formation of IFNIC cell colonies. An experiment in mice demonstrated that mechanical stress (such as a needle puncture of the heart) also induces IFNIC colony formation.
Conclusion
Myocardial infarction causes heart damage, which can lead to ventricular rupture and death. Suppressing the type I interferon response may reduce the risk of rupture, while its activation makes the heart more vulnerable. In a mouse model of MI, IFNIC cell colonies activating the IFN response were observed near rupture sites. These colonies contained macrophages and fibroblasts responsible for tissue repair. However, type I interferon inhibited fibroblast activation, reducing their ability to repair heart tissue thereby increasing the risk of rupture.
Developing new treatments aimed at suppressing the IFN response in cardiomyocytes and border zone fibroblasts after myocardial infarction could reduce the risk of heart tissue rupture without causing broad immunosuppression.
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Reference
Spatially clustered type I interferon responses at injury borderzones
