IKKε-deficient macrophages impede cardiac repair after myocardial infarction by enhancing macrophage-myofibroblast transition

Abstract The regulatory role of the inhibitor of NF-kB kinase ε (IKKε) in post-myocardial infarction (MI) inflammation remains uncertain. Using an MI mouse model, we examined the cardiac outcomes of IKKε knockout (KO) mice versus wild type. We deployed single-cell RNA sequencing (scRNA-seq) and phosphorylated protein array techniques to profile cardiac macrophages. IKKε KO mice exhibited compromised survival, heightened inflammation, pronounced cardiac fibrosis, and reduced ejection fraction. A distinct cardiac macrophage subset in IKKε KO mice demonstrated increased fibrotic markers and decreased phosphorylated p38 (p-p38) levels, implicating an enhanced macrophage-myofibroblast transition (MMT) post-MI. While cardiac inflammation is crucial in initiating compensatory pathways, the timely resolution of inflammation was impaired in the IKKε KO group, while MMT in macrophages accelerated post-MI, leading to cardiac failure. Additionally, our study highlighted the potential of 5-azacytidine (5AZ), known for its anti-inflammatory and cardiac protective properties, in restoring p-p38 in stimulated macrophages. Administering 5AZ significantly reduced MMT in cardiac macrophages of the IKKε KO group. These findings underscore the regulation of inflammation response and macrophage transition by the IKKε-p38 axis, indicating MMT as a promising therapeutic target for ischemic heart disease.