In Vivo Silencing of the Transcription Factor IRF5 Reprograms the Macrophage Phenotype and Improves Infarct Healing
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Author(s)
Courties, Gabriel
Heidt, Timo
Sebas, Matthew
Iwamoto, Yoshiko
Jeon, Derrick
Truelove, Jessica
Tricot, Benoit
Wojtkiewicz, Greg
Dutta, Partha
Sager, Hendrik B.
Date Issued
December 2013
Journal
Journal of the American College of Cardiology
Publisher
Elsevier
Citation
Courties, Gabriel, Timo Heidt, Matthew Sebas, Yoshiko Iwamoto, Derrick Jeon, Jessica Truelove, Benoit Tricot, et al. “In Vivo Silencing of the Transcription Factor IRF5 Reprograms the Macrophage Phenotype and Improves Infarct Healing.” Journal of the American College of Cardiology 63, no. 15 (April 2014): 1556–1566.
Version
Author's final manuscript
Abstract
Objectives
The aim of this study was to test whether silencing of the transcription factor interferon regulatory factor 5 (IRF5) in cardiac macrophages improves infarct healing and attenuates post–myocardial infarction (MI) remodeling.
Background
In healing wounds, the M1 toward M2 macrophage phenotype transition supports resolution of inflammation and tissue repair. Persistence of inflammatory M1 macrophages may derail healing and compromise organ functions. The transcription factor IRF5 up-regulates genes associated with M1 macrophages.
Methods
Here we used nanoparticle-delivered small interfering ribonucleic acid (siRNA) to silence IRF5 in macrophages residing in MIs and in surgically-induced skin wounds in mice.
Results
Infarct macrophages expressed high levels of IRF5 during the early inflammatory wound-healing stages (day 4 after coronary ligation), whereas expression of the transcription factor decreased during the resolution of inflammation (day 8). Following in vitro screening, we identified an siRNA sequence that, when delivered by nanoparticles to wound macrophages, efficiently suppressed expression of IRF5 in vivo. Reduction of IRF5 expression, a factor that regulates macrophage polarization, reduced expression of inflammatory M1 macrophage markers, supported resolution of inflammation, accelerated cutaneous and infarct healing, and attenuated development of post-MI heart failure after coronary ligation as measured by protease targeted fluorescence molecular tomography–computed tomography imaging and cardiac magnetic resonance imaging (p < 0.05).
Conclusions
This work identified a new therapeutic avenue to augment resolution of inflammation in healing infarcts by macrophage phenotype manipulation. This therapeutic concept may be used to attenuate post-MI remodeling and heart failure.
MIT Department
Massachusetts Institute of Technology. Institute for Medical Engineering & Science
Harvard University--MIT Division of Health Sciences and Technology
Massachusetts Institute of Technology. Department of Chemical Engineering
Koch Institute for Integrative Cancer Research at MIT
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Creative Commons Attribution-NonCommercial-NoDerivs License
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DOI of Published Version
https://doi.org/10.1016/j.jacc.2013.11.023
