title: In vivo silencing of the transcription factor IRF5 reprograms the macrophage phenotype and improves infarct healing.
abstract: OBJECTIVE
  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.
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Courties
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Timo
authors.initials: T
authors.lastname: Heidt
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Matthew
authors.initials: M
authors.lastname: Sebas
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Iwamoto
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Derrick
authors.initials: D
authors.lastname: Jeon
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Jessica
authors.initials: J
authors.lastname: Truelove
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Benoit
authors.initials: B
authors.lastname: Tricot
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Greg
authors.initials: G
authors.lastname: Wojtkiewicz
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Partha
authors.initials: P
authors.lastname: Dutta
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Hendrik B
authors.initials: HB
authors.lastname: Sager
authors.affiliation: Alnylam Pharmaceuticals, Cambridge, Massachusetts.
authors.forename: Anna
authors.initials: A
authors.lastname: Borodovsky
authors.affiliation: Alnylam Pharmaceuticals, Cambridge, Massachusetts.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Novobrantseva
authors.affiliation: Alnylam Pharmaceuticals, Cambridge, Massachusetts.
authors.forename: Boris
authors.initials: B
authors.lastname: Klebanov
authors.affiliation: Alnylam Pharmaceuticals, Cambridge, Massachusetts.
authors.forename: Kevin
authors.initials: K
authors.lastname: Fitzgerald
authors.affiliation: David H. Koch Institute for Integrative Cancer Research, Department of Chemical Engineering, Division of Health Science Technology, and Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, Massachusetts.
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Anderson
authors.affiliation: Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Peter
authors.initials: P
authors.lastname: Libby
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Filip K
authors.initials: FK
authors.lastname: Swirski
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts; Department of Systems Biology, Harvard Medical School, Boston, Massachusetts.
authors.forename: Ralph
authors.initials: R
authors.lastname: Weissleder
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts. Electronic address: mnahrendorf@mgh.harvard.edu.
authors.forename: Matthias
authors.initials: M
authors.lastname: Nahrendorf
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D050835:Interferon Regulatory Factors / Q000235:genetics* / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D009203:Myocardial Infarction / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype; D012313:RNA / Q000235:genetics*; D020257:Ventricular Remodeling
chemical_list: D050835:Interferon Regulatory Factors; C498178:Irf5 protein, mouse; D012313:RNA
keywords: IRF5; healing; heart failure; macrophage; myocardial infarction