Cell Mol Immunol. 2026 Apr 22. doi: 10.1038/s41423-026-01417-8. Online ahead of print.
ABSTRACT
Changes in the immune microenvironment are key features of ischemic heart disease. In particular, excessive inflammatory responses driven by macrophages are the primary cause of myocardial injury, impaired repair and deterioration of cardiac function following myocardial infarction (MI). We report that interleukin enhancer binding factor 3 (ILF3) is a key regulator that mediates immune responses in macrophages. We found that ILF3 expression was significantly upregulated in macrophages from AMI patients and animal models. This was accompanied by increased levels of inflammation and cardiac dysfunction. ILF3 deficiency in myocardial infarction mice promoted the resolution of inflammatory responses while improving cardiac function and mitigating adverse remodeling. Mechanistically, macrophage ILF3 inhibits Trim21-mediated ubiquitination and degradation of HNRNPA2B1 (heterogeneous nuclear ribonucleoprotein A2B1) at lysine 112 through binding to the RRM1 and RRM2 domains of HNRNPA2B1. The ILF3/HNRNPA2B1 axis enhances the stability of Irak4 mRNA through m6A modification, activating the c-jun/c-fos pathway, leading to early inflammatory responses following MI, and promoting myocardial injury and adverse remodeling after infarction. Finally, our results suggest that targeting HNRNPA2B1 and Irak4 effectively improves myocardial injury and cardiac repair post-MI. In summary, our findings underscore the critical role of macrophage ILF3 in mediating postinfarction inflammation in myocardial injury. These findings suggest that inhibition of macrophage ILF3 may be an important target for the treatment of ischemic myocardial injury and inflammation. During the inflammatory phase of myocardial infarction, ILF3 levels are elevated in macrophages. Macrophage ILF3 inhibits the ubiquitination and degradation of HNRNPA2B1. The latter increases the stability of Irak4 mRNA through m6A modification, activating the c-jun/c-fos pathway, leading to early inflammatory responses, and promoting myocardial injury and adverse remodeling. When ILF3 is absent in macrophages, HNRNPA2B1 is degraded by Trim21-mediated ubiquitination, subsequently inhibiting inflammation-related signaling pathways, alleviating myocardial damage, and promoting repair.
PMID:42020716 | DOI:10.1038/s41423-026-01417-8