Abstract Body: Introduction: Macrophages (Mφ) and their phenotypic polarization play essential roles in modulating cardiac inflammation and recovery after myocardial infarction (MI). Interleukin-10 (IL-10) is a potent immunomodulatory cytokine that directs Mφ polarization to beneficial reparative phenotypes and is widely investigated in diseases involving extensive inflammation. However, high-dose IL-10 treatment may not lead to the expected therapeutic outcome, raising the question of whether IL-10 has dose-dependent effects on Mφ polarization and cardiac remodeling post-MI.
Hypothesis: IL-10 can program Mφ phenotypes under inflammation and has functional impact in cardiac remodeling post-MI in dose-dependent manner.
Goals: We use RAW264.7 Mφ and mouse permanent MI models to test our hypothesis.
Approach: We applied 25-1000 ng/mL IL-10 in vitro before or after inducing M1 (with interferon-g) and M2 (with interleukin-4) polarization for pro-inflammatory and anti-inflammatory phenotypes, respectively. We intramyocardially administered 25-2000 ng IL-10 in vivo immediately after inducing MI and examined cardiac function, inflammatory responses, fibrosis and revascularization for 6 weeks (n=5/group).
Results: IL-10 at 100-250 ng/mL directed Mφ phenotype shift from M1 to M2 most effectively after inducing polarization in vitro (both p<0.01); groups with ≥500 ng/mL IL-10 exhibited high M1/low M2 phenotypes, similar to no IL-10 controls. Cells treated with ≥100 ng/mL IL-10 before polarization exhibited a notable reduction in M1 phenotype after induction (all p<0.05). Echocardiography showed that with single IL-10 administration, only 250 ng IL-10 notaly improved left ventricular (LV) function and reduced LV chamber size compared with the saline control (p<0.05) whilst ≥1000 ng caused a transient negative impact in LV function at 5 days post-MI (p<0.05), Phagocyte infiltration at MI was notably diminished in ≥100 ng groups at 6 weeks post-MI (all p<0.05). Only 250 ng IL-10 led to a notable 53% reduction in LV fibrosis (p=0.05) and nearly 200% increase in CD31+ cell counts at MI (p=0.013).
Conclusion: Our results suggest an optimal range of IL-10 doses for macrophage polarization and cardiac benefits post-MI, with risks of side effects from IL-10 overdose.