Targeting NR4A1 (Nur77) in Macrophage Polarization: Molecular Mechanisms and Translational Prospects for Cardiac Repair After Myocardial Infarction

Sterile inflammation in the course of myocardial infarction can be a factor contributing to cardiac remodeling and heart failure. To break this pathological vicious circle, the polarization of macrophages to a reparative M2 phenotype, to start the tissue repair process and alleviate the inflammation, is the key. Recent studies have shown that the nuclear receptor subfamily 4 group A (NR4A) orphan nuclear receptor family, particularly nuclear receptor subfamily 4 group A member 1 (NR4A1/NUR77), plays a role in macrophage reprogramming in relation to the modulation of macrophage polarization. Herein, we discuss in detail the specific pathways regulated by NR4A receptors during cellular reprogramming, including the nuclear factor kappa B (NF-κB) pathway and the oxidative phosphorylation pathway. We list below the beneficial effects of NR4A-treated macrophages in the hypoxic cardiac tissue, including their essential contribution to the formation of a neovascular network, the maintenance of the extracellular matrix by fibroblasts, and the direct rescue of remaining cardiomyocytes. In addition, given the translational potential of targeted therapy with immunomodulatory molecules against NR4A, we also review the design of macrophage-specific nanodelivery systems and the creation of novel small-molecule activators for ischemic cardiovascular diseases to identify therapeutic targets for cardiac repair based on NR4A.