In Vivo Silencing of the Transcription Factor IRF5 Reprograms the Macrophage Phenotype and Improves Infarct Healing

• Published in: Journal of the American College of Cardiology Vol. 63; no. 15; pp. 1556 - 1566
• Main Authors: Courties, Gabriel, PhD, Heidt, Timo, MD, Sebas, Matthew, BS, Iwamoto, Yoshiko, BS, Jeon, Derrick, MS, Truelove, Jessica, BS, Tricot, Benoit, MS, Wojtkiewicz, Greg, MS, Dutta, Partha, PhD, Sager, Hendrik B., MD, Borodovsky, Anna, PhD, Novobrantseva, Tatiana, PhD, Klebanov, Boris, PhD, Fitzgerald, Kevin, PhD, Anderson, Daniel G., PhD, Libby, Peter, MD, Swirski, Filip K., PhD, Weissleder, Ralph, MD, PhD, Nahrendorf, Matthias, MD, PhD
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 22-04-2014; Elsevier; Elsevier Limited
• Subjects: Animals; Atherosclerosis; Biological and medical sciences; Cardiology; Cardiology. Vascular system; Cardiovascular; Disease Models, Animal; Gene expression; Gene Expression Regulation; Genotype & phenotype; healing; Heart; Heart attacks; Heart failure; Interferon Regulatory Factors - genetics; Interferon Regulatory Factors - metabolism; Internal Medicine; IRF5; macrophage; Macrophages - metabolism; Medical sciences; Mice; Myocardial Infarction - genetics; Myocardial Infarction - metabolism; Myocardial Infarction - physiopathology; myocardial infarction; Myocardium - metabolism; Myocardium - pathology; Nanoparticles; Phenotype; RNA - genetics; Rodents; Studies; Tissue engineering; Transcription factors; Ventricular Remodeling; Wound healing; heart failure; IL; lipidoid nanoparticle; myocardial infarction; interferon regulatory factor 5; macrophage; siRNA; TNF; LNP; healing; MMP; small interfering ribonucleic acid; tumor necrosis factor; fluorescence reflectance imaging; tissue inhibitor of metalloproteinase; myocardial infarction; matrix metalloproteinase; IRF5; FRI; interleukin; MI; TIMP; In vivo; Improvement; Phenotype; Treatment; Infarct; Healing agent; Cardiovascular disease; Circulatory system; Cardiology; Transcription factor; Cicatrization; Macrophage
• ISSN: 0735-1097; 1558-3597
• DOI: 10.1016/j.jacc.2013.11.023

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.