Abstract 13411: Overexpression of Interleukin-10 in Murine Macrophages for Anti-Inflammatory Therapy in Myocarditis
Objectives: Myocarditis is a multifactorial disease and macrophages play an essential role in the pathogenesis of myocardial inflammation. A specific and approved therapy is often missing or limited by systemic side-effects. Interleukin-10 (IL-10) represents a strong anti-inflammatory chemokine. We overexpressed IL-10 in murine macrophages for targeted therapy in myocarditis in vivo.
Methods: Murine CD11b+ macrophages have been isolated from peritoneum and IL-10 was overexpressed by mRNA nucleofection. In A/J mice myocarditis was induced by subcutaneous immunization with cardiac troponin I. IL-10 overexpressing macrophages were injected intravenously into A/J mice after induction of myocarditis (n=10). MOCK transfected macrophages were used as controls (n=10). Myocardial inflammation was assessed histologically by H & E staining. Treadmill exercise testing was employed to evaluate physical performance, while cardiac function was quantified by echocardiography.
Results: In vitro overexpression of IL-10 in macrophages resulted in a 7-fold increased IL-10 production after 6h and persisted for several days. In vivo we were able to detect increased IL-10 level in both, the myocardium and the supernatant of splenocytes from mice treated with IL-10 overexpressing macrophages. Inflammation was significantly lower in treated mice than in the control group (histological score 2.2 ± 0.6 vs. 3.5 ± 0.5; p=0.02). Immunohistochemical staining showed less CD3+ lymphocytes and CD68+ macrophages. Mice treated with IL-10 overexpressing macrophages presented a significantly better performance on exercise testing than the control group (5.6 ± 0.7 km/d vs. 3.8 ± 0.6 km/d; p=0.02). Echocardiography revealed a trend towards improved cardiac function in treated mice (fractional shortening 38.8 ± 1.4 % vs. 34.6 ± 2.0 %; p=0.16).
Conclusion: We demonstrate that overexpression of IL-10 in macrophages could reduce inflammation and improve cardiac performance in a murine model of myocarditis. The use of genetically modified macrophages could facilitate targeted therapy of local inflammatory processes to reduce systemic side-effects. As mRNA nucleofection has been approved for in vivo use in humans this therapy could be transferred into a clinical setting.
- © 2010 by American Heart Association, Inc.