Florian Leuschner1, Gabriel Courties2, Partha Dutta2, Luke J Mortensen2, Rostic Gorbatov2, Brena Sena2, Tatiana I Novobrantseva3, Anna Borodovsky3, Kevin Fitzgerald3, Victor Koteliansky4, Yoshiko Iwamoto2, Marina Bohlender5, Soeren Meyer5, Felix Lasitschka6, Benjamin Meder5, Hugo A Katus5, Charles Lin2, Peter Libby7, Filip K Swirski2, Daniel G Anderson8, Ralph Weissleder9, Matthias Nahrendorf10. 1. 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. 2. Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Simches Research Building, 185 Cambridge Street, Boston, MA 02114, USA. 3. Alnylam Pharmaceuticals, 300 3rd Street, Cambridge, MA 02142, USA. 4. Department of Chemical Engineering, Massachusetts Institute of Technology, University Hospital Heidelberg, Heidelberg, Germany. 5. 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. 6. Institute of Pathology, University Hospital Heidelberg, Im Neuenheimer Feld 220/221, Heidelberg 69120, Germany. 7. Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA. 8. 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. 9. 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. 10. 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.
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. METHODS AND 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). CONCLUSION: 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. Published on behalf of the European Society of Cardiology. All rights reserved.
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. METHODS AND 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). CONCLUSION: 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. Published on behalf of the European Society of Cardiology. All rights reserved.
Authors: Leslie T Cooper; Kenneth L Baughman; Arthur M Feldman; Andrea Frustaci; Mariell Jessup; Uwe Kuhl; Glenn N Levine; Jagat Narula; Randall C Starling; Jeffrey Towbin; Renu Virmani Journal: J Am Coll Cardiol Date: 2007-11-06 Impact factor: 24.094
Authors: Stefan Göser; Martin Andrassy; Sebastian J Buss; Florian Leuschner; Christian H Volz; Renate Ottl; Stefan Zittrich; Natascha Blaudeck; Stefan E Hardt; Gabriele Pfitzer; Noel R Rose; Hugo A Katus; Ziya Kaya Journal: Circulation Date: 2006-10-02 Impact factor: 29.690
Authors: Matthias Nahrendorf; David E Sosnovik; Peter Waterman; Filip K Swirski; Ashvin N Pande; Elena Aikawa; Jose-Luiz Figueiredo; Mikael J Pittet; Ralph Weissleder Journal: Circ Res Date: 2007-03-22 Impact factor: 17.367
Authors: Stefan Göser; Renate Ottl; Alexander Brodner; Thomas J Dengler; Jan Torzewski; Kensuke Egashira; Noel R Rose; Hugo A Katus; Ziya Kaya Journal: Circulation Date: 2005-11-29 Impact factor: 29.690
Authors: J W Mason; J B O'Connell; A Herskowitz; N R Rose; B M McManus; M E Billingham; T E Moon Journal: N Engl J Med Date: 1995-08-03 Impact factor: 91.245
Authors: Ziya Kaya; Stefan Göser; Sebastian J Buss; Florian Leuschner; Renate Ottl; Jin Li; Mirko Völkers; Stefan Zittrich; Gabriele Pfitzer; Noel R Rose; Hugo A Katus Journal: Circulation Date: 2008-10-27 Impact factor: 29.690
Authors: Akin Akinc; Andreas Zumbuehl; Michael Goldberg; Elizaveta S Leshchiner; Valentina Busini; Naushad Hossain; Sergio A Bacallado; David N Nguyen; Jason Fuller; Rene Alvarez; Anna Borodovsky; Todd Borland; Rainer Constien; Antonin de Fougerolles; J Robert Dorkin; K Narayanannair Jayaprakash; Muthusamy Jayaraman; Matthias John; Victor Koteliansky; Muthiah Manoharan; Lubomir Nechev; June Qin; Timothy Racie; Denitza Raitcheva; Kallanthottathil G Rajeev; Dinah W Y Sah; Jürgen Soutschek; Ivanka Toudjarska; Hans-Peter Vornlocher; Tracy S Zimmermann; Robert Langer; Daniel G Anderson Journal: Nat Biotechnol Date: 2008-04-27 Impact factor: 54.908
Authors: Jun-Ichiro Koga; Toshiaki Nakano; James E Dahlman; Jose-Luiz Figueiredo; Hengmin Zhang; Julius Decano; Omar F Khan; Tomiharu Niida; Hiroshi Iwata; Jon C Aster; Hideo Yagita; Daniel G Anderson; C Keith Ozaki; Masanori Aikawa Journal: Arterioscler Thromb Vasc Biol Date: 2015-09-24 Impact factor: 8.311
Authors: Christine S Zuern; Britta Walker; Martina Sauter; Malte Schaub; Madhumita Chatterjee; Karin Mueller; Dominik Rath; Sebastian Vogel; Roland Tegtmeyer; Peter Seizer; Tobias Geisler; Reinhard Kandolf; Florian Lang; Karin Klingel; Meinrad Gawaz; Oliver Borst Journal: Clin Res Cardiol Date: 2015-05-26 Impact factor: 5.460
Authors: Wolfgang Poller; Stefanie Dimmeler; Stephane Heymans; Tanja Zeller; Jan Haas; Mahir Karakas; David-Manuel Leistner; Philipp Jakob; Shinichi Nakagawa; Stefan Blankenberg; Stefan Engelhardt; Thomas Thum; Christian Weber; Benjamin Meder; Roger Hajjar; Ulf Landmesser Journal: Eur Heart J Date: 2018-08-01 Impact factor: 29.983