Cytosolic DNA Sensing Promotes Macrophage Transformation and Governs Myocardial Ischemic Injury
Background—Myocardium irreversibly injured by ischemic stress must be efficiently repaired to maintain tissue integrity and contractile performance. Macrophages play critical roles in this process. These cells transform across a spectrum of phenotypes to accomplish diverse functions ranging from mediating the initial inflammatory responses that clear damaged tissue to subsequent reparative functions that help rebuild replacement tissue. Although macrophage transformation is crucial to myocardial repair, events governing this transformation are poorly understood.
Methods—Here, we set out to determine whether innate immune responses triggered by cytoplasmic DNA play a role.
Results—We report that ischemic myocardial injury, and the resulting release of nucleic acids, activates the recently described cGAS (GMP-AMP synthase)-STING (stimulator of interferon genes) pathway. Animals lacking cGAS display significantly improved early survival post-MI, diminished pathological remodeling including ventricular rupture, enhanced angiogenesis, and preserved ventricular contractile function. Furthermore, cGAS loss-of-function abolishes the induction of key inflammatory programs such as iNOS and promotes the transformation of macrophages to a reparative phenotype, which results in enhanced repair and improved hemodynamic performance.
Conclusions—These results reveal, for the first time, that the cytosolic DNA receptor cGAS functions during cardiac ischemia as a pattern recognition receptor in the sterile immune response. Further, we report that this pathway governs macrophage transformation, thereby regulating post-injury cardiac repair. As modulators of this pathway are currently in clinical use, our findings raise the prospect of new treatment options to combat ischemic heart disease and its progression to heart failure.
- Received August 9, 2017.
- Revision received January 5, 2018.
- Accepted January 12, 2018.