title: Silencing of CCR2 in myocarditis.
abstract: BACKGROUND
  Myocarditis is characterized by inflammatory cell infiltration of the heart and subsequent deterioration of cardiac function. Monocytes are the most prominent population of accumulating leucocytes. We investigated whether in vivo administration of nanoparticle-encapsulated siRNA targeting chemokine (C-C motif) receptor 2 (CCR2)-a chemokine receptor crucial for leucocyte migration in humans and mice--reduces inflammation in autoimmune myocarditis.
  
  
  RESULTS
  In myocardium of patients with myocarditis, CCL2 mRNA levels and CCR2(+) cells increased (P < 0.05), motivating us to pursue CCR2 silencing. Flow cytometric analysis showed that siRNA silencing of CCR2 (siCCR2) reduced the number of Ly6C(high) monocytes in hearts of mice with acute autoimmune myocarditis by 69% (P < 0.05), corroborated by histological assessment. The nanoparticle-delivered siRNA was not only active in monocytes but also in bone marrow haematopoietic progenitor cells. Treatment with siCCR2 reduced the migration of bone marrow granulocyte macrophage progenitors into the blood. Cellular magnetic resonance imaging (MRI) after injection of macrophage-avid magnetic nanoparticles detected myocarditis and therapeutic effects of RNAi non-invasively. Mice with acute myocarditis showed enhanced macrophage MRI contrast, which was prevented by siCCR2 (P < 0.05). Follow-up MRI volumetry revealed that siCCR2 treatment improved ejection fraction (P < 0.05 vs. control siRNA-treated mice).
  
  
  CONCLUSIONS
  This study highlights the importance of CCR2 in the pathogenesis of myocarditis. In addition, we show that siCCR2 affects leucocyte progenitor trafficking. The data also point to a novel therapeutic strategy for the treatment of myocarditis.
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Simches Research Building, 185 Cambridge Street, Boston, MA 02114, USA Department of Cardiology, Medical University Hospital Heidelberg, Im Neuenheimer Feld 410, Heidelberg D-69120, Germany DZHK (German Centre for Cardiovascular Research), Partner Site Heidelberg/Mannheim, Heidelberg, Germany mnahrendorf@mgh.harvard.edu florian.leuschner@med.uni-heidelberg.de.
authors.forename: Florian
authors.initials: F
authors.lastname: Leuschner
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Simches Research Building, 185 Cambridge Street, Boston, MA 02114, USA.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Courties
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Simches Research Building, 185 Cambridge Street, Boston, MA 02114, USA.
authors.forename: Partha
authors.initials: P
authors.lastname: Dutta
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Simches Research Building, 185 Cambridge Street, Boston, MA 02114, USA.
authors.forename: Luke J
authors.initials: LJ
authors.lastname: Mortensen
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Simches Research Building, 185 Cambridge Street, Boston, MA 02114, USA.
authors.forename: Rostic
authors.initials: R
authors.lastname: Gorbatov
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Simches Research Building, 185 Cambridge Street, Boston, MA 02114, USA.
authors.forename: Brena
authors.initials: B
authors.lastname: Sena
authors.affiliation: Alnylam Pharmaceuticals, 300 3rd Street, Cambridge, MA 02142, USA.
authors.forename: Tatiana I
authors.initials: TI
authors.lastname: Novobrantseva
authors.affiliation: Alnylam Pharmaceuticals, 300 3rd Street, Cambridge, MA 02142, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Borodovsky
authors.affiliation: Alnylam Pharmaceuticals, 300 3rd Street, Cambridge, MA 02142, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Fitzgerald
authors.affiliation: Department of Chemical Engineering, Massachusetts Institute of Technology, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Victor
authors.initials: V
authors.lastname: Koteliansky
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Simches Research Building, 185 Cambridge Street, Boston, MA 02114, USA.
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Iwamoto
authors.affiliation: Department of Cardiology, Medical University Hospital Heidelberg, Im Neuenheimer Feld 410, Heidelberg D-69120, Germany DZHK (German Centre for Cardiovascular Research), Partner Site Heidelberg/Mannheim, Heidelberg, Germany.
authors.forename: Marina
authors.initials: M
authors.lastname: Bohlender
authors.affiliation: Department of Cardiology, Medical University Hospital Heidelberg, Im Neuenheimer Feld 410, Heidelberg D-69120, Germany DZHK (German Centre for Cardiovascular Research), Partner Site Heidelberg/Mannheim, Heidelberg, Germany.
authors.forename: Soeren
authors.initials: S
authors.lastname: Meyer
authors.affiliation: Institute of Pathology, University Hospital Heidelberg, Im Neuenheimer Feld 220/221, Heidelberg 69120, Germany.
authors.forename: Felix
authors.initials: F
authors.lastname: Lasitschka
authors.affiliation: Department of Cardiology, Medical University Hospital Heidelberg, Im Neuenheimer Feld 410, Heidelberg D-69120, Germany DZHK (German Centre for Cardiovascular Research), Partner Site Heidelberg/Mannheim, Heidelberg, Germany.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Meder
authors.affiliation: Department of Cardiology, Medical University Hospital Heidelberg, Im Neuenheimer Feld 410, Heidelberg D-69120, Germany DZHK (German Centre for Cardiovascular Research), Partner Site Heidelberg/Mannheim, Heidelberg, Germany.
authors.forename: Hugo A
authors.initials: HA
authors.lastname: Katus
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Simches Research Building, 185 Cambridge Street, Boston, MA 02114, USA.
authors.forename: Charles
authors.initials: C
authors.lastname: Lin
authors.affiliation: Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Libby
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Simches Research Building, 185 Cambridge Street, Boston, MA 02114, USA.
authors.forename: Filip K
authors.initials: FK
authors.lastname: Swirski
authors.affiliation: Department of Chemical Engineering, Massachusetts Institute of Technology, University Hospital Heidelberg, Heidelberg, Germany David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA Division of Health Science Technology, Massachusetts Institute of Technology, Boston, MA, USA Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Boston, MA, USA.
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Anderson
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Simches Research Building, 185 Cambridge Street, Boston, MA 02114, USA Department of Systems Biology, Harvard Medical School, Boston, MA, USA.
authors.forename: Ralph
authors.initials: R
authors.lastname: Weissleder
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Simches Research Building, 185 Cambridge Street, Boston, MA 02114, USA mnahrendorf@mgh.harvard.edu florian.leuschner@med.uni-heidelberg.de.
authors.forename: Matthias
authors.initials: M
authors.lastname: Nahrendorf
mesh_terms: D000328:Adult; D000818:Animals; D001327:Autoimmune Diseases / Q000628:therapy*; D002465:Cell Movement; D018932:Chemokine CCL2 / Q000235:genetics* / Q000378:metabolism; D005260:Female; D006412:Hematopoietic Stem Cells / Q000378:metabolism / Q000502:physiology; D006801:Humans; D018810:Magnetic Resonance Angiography; D008297:Male; D051379:Mice; D009000:Monocytes / Q000378:metabolism; D009205:Myocarditis / Q000628:therapy*; D053758:Nanoparticles; D034622:RNA Interference / Q000502:physiology; D034741:RNA, Small Interfering / Q000494:pharmacology*
chemical_list: D018932:Chemokine CCL2; D034741:RNA, Small Interfering
keywords: Inflammation; Molecular imaging; Myocarditis; Nanoparticle; siRNA