CD14 blockade in a translational model of reperfused ST-elevation myocardial infarction with key clinical features.

CD14 is a widely validated marker for monocyte/macrophage activity as well as an inflammatory biomarker and upstream regulator of macrophage activity. We herein test the hypothesis that interventional CD14 blockade with a murine analogue of atibuclimab, an anti-CD14 antibody, which has recently been reported to have a favorable safety profile, prevents secondary immunological exacerbation of cardiac injury in a translational mouse model of reperfused ST-elevation myocardial infarction (STEMI) with key clinical features. We report multiomic mechanistic and translation-informing evidence that CD14 blockade downregulated macrophagic pro-inflammatory and tissue remodeling processes without suppression of monocyte-macrophage infiltration or repair, and prevented the post-acute progression of LV dysfunction, dilatation, and haemodynamic decompensation. These data provide the first evidence to support a clinically practicable targeted immunomodulatory strategy of CD14 blockade initiated at reperfusion for the prevention of chronic immunological progression towards ischemic heart failure using multiple clinical modalities. These findings also provide new insights into the pleiotropic roles of CD14 in ischemic heart failure following ischemia injury-reperfusion.