TY - JOUR
T1 - Cytosolic DNA sensing promotes macrophage transformation and governs myocardial ischemic injury
AU - Cao, Dian J
AU - Schiattarella, Gabriele G.
AU - Villalobos, Elisa
AU - Jiang, Nan
AU - May, Herman I.
AU - Li, Tuo
AU - Chen, Zhijian
AU - Gillette, Thomas G.
AU - Hill, Joseph A
N1 - Funding Information:
This work was supported by grants from the National Institutes of Health (K08 HL116801 to Dr Cao; HL-120732, HL-126012, and HL-128215 to Dr Hill), American Heart Association (14SFRN20510023, 14SFRN20670003 to Dr Hill), Fondation Leducq (11CVD04 to Dr Hill), and Cancer Prevention and Research Institute of Texas (RP110486P3 to Dr Hill).
Publisher Copyright:
©2018 American Heart Association, Inc.
PY - 2018/6/12
Y1 - 2018/6/12
N2 - 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, along with the resulting release of nucleic acids, activates the recently described cyclic GMP-AMP synthase-stimulator of interferon genes pathway. Animals lacking cyclic GMP-AMP synthase display significantly improved early survival after myocardial infarction and diminished pathological remodeling, including ventricular rupture, enhanced angiogenesis, and preserved ventricular contractile function. Furthermore, cyclic GMP-AMP synthase loss of function abolishes the induction of key inflammatory programs such as inducible nitric oxide synthase 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 cyclic GMP-AMP synthase functions during cardiac ischemia as a pattern recognition receptor in the sterile immune response. Furthermore, we report that this pathway governs macrophage transformation, thereby regulating postinjury cardiac repair. Because 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.
AB - 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, along with the resulting release of nucleic acids, activates the recently described cyclic GMP-AMP synthase-stimulator of interferon genes pathway. Animals lacking cyclic GMP-AMP synthase display significantly improved early survival after myocardial infarction and diminished pathological remodeling, including ventricular rupture, enhanced angiogenesis, and preserved ventricular contractile function. Furthermore, cyclic GMP-AMP synthase loss of function abolishes the induction of key inflammatory programs such as inducible nitric oxide synthase 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 cyclic GMP-AMP synthase functions during cardiac ischemia as a pattern recognition receptor in the sterile immune response. Furthermore, we report that this pathway governs macrophage transformation, thereby regulating postinjury cardiac repair. Because 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.
KW - DNA
KW - cGAS
KW - macrophages
KW - myocardial infarction
KW - ventricular remodeling
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U2 - 10.1161/CIRCULATIONAHA.117.031046
DO - 10.1161/CIRCULATIONAHA.117.031046
M3 - Article
C2 - 29437120
AN - SCOPUS:85046750225
SN - 0009-7322
VL - 137
SP - 2613
EP - 2634
JO - Circulation
JF - Circulation
IS - 24
ER -