Zhang Jing J, Rizk Rodrigue, Li Xiaoping, Lee Brandon G, Matthies Mason L, Bietz Kennedy A, Kim Kang, Huard Johnny, Wang Yadong, Chen William C W
Division of Basic Biomedical Sciences, Sanford School of Medicine, University of South Dakota, Vermillion, SD, United States.
Department of Computer Science, University of South Dakota, Vermillion, SD, United States.
Front Physiol. 2025 Jan 15;15:1481460. doi: 10.3389/fphys.2024.1481460. eCollection 2024.
Interleukin-10 (IL-10) is a potent immunomodulatory cytokine widely explored as a therapeutic agent for diseases, including myocardial infarction (MI). High-dose IL-10 treatment may not achieve expected outcomes, raising the question of whether IL-10 has dose-dependency, or even uncharted side-effects from overdosing. We hypothesized that IL-10 has dose-dependent effects on macrophage (Mφ) phenotypic transition and cardiac remodeling after MI.
Using RAW264.7 monocyte models, we examined whether administering differential doses of exogenous IL-10 (0-1,000 ng/mL) perturbs classic M1 (pro-inflammatory) and M2 (anti-inflammatory) phenotypes of polarized Mφ or even alters the phenotypic transition of prospective M1 and M2 polarization. We then investigated the impact of single intramyocardial IL-10 administration on cardiac function, structure, and inflammation post-MI, using a mouse MI model.
Compared with 0-ng/mL control, 250-ng/mL IL-10 had the strongest overall effects in decreasing M1 and increasing M2 phenotypes on polarized Mφ while ≥500-ng/mL IL-10 dampened M1 polarization and augmented native IL-10 secretion more effectively than low doses . Echocardiography revealed that the 250-ng group had consistently higher contractile function and lower left ventricular (LV) dilatation than the saline control over 6 weeks while ≥1,000-ng groups exhibited transient lower LV ejection fraction at 5 days post-MI . Moreover, different doses of IL-10 differentially modulated myocardial gene expression, phagocytic cell infiltration at the infarct, LV fibrosis, and revascularization post-MI, with some, but not all, doses exerting beneficial effects.
Our study suggested that IL-10 has an effective dose range on Mφ phenotypes, and intramyocardial IL-10 treatment may trigger cardioprotective or unwanted effects post-MI in a dose-dependent manner.
白细胞介素-10（IL-10）是一种强效免疫调节细胞因子，作为包括心肌梗死（MI）在内的多种疾病的治疗药物，已得到广泛研究。高剂量IL-10治疗可能无法达到预期效果，这引发了关于IL-10是否具有剂量依赖性，甚至过量使用是否存在未知副作用的问题。我们假设IL-10对心肌梗死后巨噬细胞（Mφ）表型转变和心脏重塑具有剂量依赖性作用。
使用RAW264.7单核细胞模型，我们研究了给予不同剂量的外源性IL-10（0 - 1000 ng/mL）是否会干扰极化Mφ的经典M1（促炎）和M2（抗炎）表型，甚至改变预期M1和M2极化的表型转变。然后，我们使用小鼠心肌梗死模型研究了心肌内单次注射IL-10对心肌梗死后心脏功能、结构和炎症的影响。
与0 ng/mL对照组相比，250 ng/mL IL-10在降低极化Mφ的M1表型和增加M2表型方面具有最强的总体效果，而≥500 ng/mL IL-10比低剂量更有效地抑制M1极化并增强内源性IL-10分泌。超声心动图显示，在6周内，250 ng组的收缩功能始终高于生理盐水对照组，左心室（LV）扩张程度更低，而≥1000 ng组在心肌梗死后5天表现出短暂的左心室射血分数降低。此外，不同剂量的IL-10对心肌基因表达、梗死部位吞噬细胞浸润、左心室纤维化和心肌梗死后血管再生有不同的调节作用，部分但并非所有剂量都具有有益作用。
我们的研究表明，IL-10对Mφ表型具有有效剂量范围，心肌内注射IL-10治疗可能以剂量依赖方式在心肌梗死后引发心脏保护或不良影响。
