Abstract
Recent research has shown that reparative (alternatively activated or M2) macrophages play a role in repair of damaged tissues, including the infarcted hearts. Administration of IL-4 is known to augment M2 macrophages. This translational study thus aimed to investigate whether IL-4 administration is useful for the treatment of myocardial infarction. Long-acting IL-4 complex (IL-4c; recombinant IL-4 mixed with anti-IL-4 monoclonal antibody as a stabilizer) was administered after coronary artery ligation in mice. It was observed that IL-4c administration increased accumulation of CD206+F4/80+ M2-like macrophages predominantly in the injured myocardium, compared to the control. Sorted cardiac M2-like macrophages highly expressed wide-ranging tissue repair-related genes. Indeed, IL-4c administration enhanced cardiac function in association with reduced infarct size and enhanced tissue repair (strengthened connective tissue formation, improved microvascular formation and attenuated cardiomyocyte hypertrophy). Experiments using Trib1−/− mice that had a depleted ability to develop M2 macrophages and other in-vitro studies supported that these IL-4-mediated effects were induced via M2-like macrophages. On the other hand, when administered at Day 28 post-MI, the effects of IL-4c were diminished, suggesting a time-frame for IL-4 treatment to be effective. These data represent proof-of-concept of efficacy of IL-4 treatment for acute myocardial infarction, encouraging its further development.
Highlights
Distinct types of monocytes and macrophages play a role in initiation, maintenance, and resolution of myocardial inflammation post-MI4–8, which control cardiac repair and adverse ventricular remodeling
Interleukin 4 (IL-4) complex (IL-4c; a mixture of 5 μg recombinant mouse IL-4 and 25 μg anti-IL-4 monoclonal antibody dissolved in PBS; IL-4 group) or PBS only (PBS group) was injected intraperitoneally at 1 hour after left coronary artery ligation in adult C57BL/6 mice
Immunohistolabeling demonstrated that IL-4c treatment achieved a more extensive increase of CD206+ cells at Day 7 post-MI, compared to the PBS control, with the most evident increase being seen in the infarct area (Fig. 1a,b and Supplementary Fig. S1)
Summary
Distinct types of monocytes and macrophages play a role in initiation, maintenance, and resolution of myocardial inflammation post-MI4–8, which control cardiac repair and adverse ventricular remodeling. Along with the reduction of the increased M1 macrophages, the number of reparative, anti-inflammatory (alternatively activated or M2) Ly-6CloCD206+ macrophages increases in the heart, with a peak at Day 5–7 post-MI4–8 These cells play a role in the resolution of acute inflammation as well as facilitation of prompt extracellular matrix synthesis by activating fibroblasts, together resulting in the formation of fibrotic scar tissues to reinforce the vulnerable ventricular wall that had lost cardiomyocytes[5,6,7,8,9]. Previous studies have reported several methods to increase cardiac M2 macrophages, including intramyocardial injection of microparticles loaded with fibroblast growth factor-2 with hepatocyte growth factor[12], intravenous injection of phosphatidylserine-presenting liposomes[13], intramyocardial injection of FGF-914, administration of superagonistic CD28-specific monoclonal antibodies[15], and intramyocardial transplantation of mesenchymal stem cells[16] These are technically challenging and none of them has been established in the clinical arena yet. Repurposing IL-4, which has already been shown to be safe in clinical trials of cancer treatment[20,21,22,23,24], will represent a “low-risk high-return” development of a new biological drug for the treatment of MI
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