Classically and alternatively activated macrophages contribute to tissue remodelling after myocardial infarction

Abstract Introduction: An important goal in cardiology is to minimize myocardial necrosis and to support a discrete but resilient scar formation after myocardial infarction (MI). Macrophages are a type of cells which influence cardiac remodelling during MI. Therefore, the goal of the present study was to investigate their transcriptional profile and to identify the type of activation during scar tissue formation. Methods: Ligature of the left anterior descending coronary artery (LAD) was performed in mice. Macrophages were isolated from infarcted tissue using magnetic cell sorting after 5d. The total RNA of macrophages was subjected to microarray analysis and compared with RNA from MI and LV-control. mRNA abundance of relevant targets was validated by quantitative real-time PCR 2d, 5d and 10d after MI (qRT-PCR). Immunohistochemistry was performed to localize activation type-specific proteins. Results: The genome scan revealed 68 targets predominantly expressed by macrophages after MI. Among these targets, an increased mRNA abundance of genes, involved in both the classically (tumor necrosis factor alpha, interleukin 6, interleukin 1beta) and the alternatively (arginase 1 and 2, mannose receptor C type 1, chitinase 3-like 3) activated phenotype of macrophages, was found 5d after MI. This observation was confirmed by qRT-PCR. Using immunohistochemistry, we confirmed that tumor necrosis factor alpha, representing the classical activation, is strongly transcribed early after ligature (2d). It was decreased after 5d and 10d. 5d after MI we found a fundamental change towards alternative activation of macrophages with upregulation of arginase 1. Conclusion: Our results demonstrate that macrophages are differentially activated during different phases of scar tissue formation after myocardial infarction. During the early inflammatory phase macrophages are predominantly classically activated, whereas their phenotype changes during the important transition from inflammation to scar tissue formation into an alternatively activated type