Silencing of CCR2 in myocarditis
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Leuschner, Florian
Courties, Gabriel
Dutta, Partha
Mortensen, Luke
Gorbatov, Rostic
Sena, Brena
Novobrantseva, Tatiana
Borodovsky, Anna
Fitzgerald, Kevin
Koteliansky, Victor
Iwamoto, Yoshiko
Bohlender, Marina
Meyer, Soeren
Lasitschka, Felix
Meder, Benjamin
Katus, Hugo
Lin, Charles
Libby, Peter
Swirski, Filip
Anderson, Daniel
Weissleder, Ralph
Nahrendorf, Matthias
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https://doi.org/10.1093/eurheartj/ehu225Metadata
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Leuschner, Florian, Gabriel Courties, Partha Dutta, Luke J. Mortensen, Rostic Gorbatov, Brena Sena, Tatiana I. Novobrantseva, et al. 2014. “Silencing of CCR2 in Myocarditis.” European Heart Journal 36 (23): 1478–88. https://doi.org/10.1093/eurheartj/ehu225.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.Citable link to this page
http://nrs.harvard.edu/urn-3:HUL.InstRepos:41384192
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