# CD14 Blockade Modulates Macrophage-Mediated Immunological Injury in a Translational Model of Reperfused ST-Segment Elevation Myocardial Infarction

## TL;DR

Blocking CD14 at reperfusion in a heart attack model reduces long-term heart damage without weakening the immune system.

## Contribution

First preclinical evidence that CD14 blockade at reperfusion prevents chronic cardiac injury in STEMI.

## Key findings

- CD14 blockade with an antibody reduced left ventricular dysfunction and heart failure progression over 28 days.
- Multiomic analysis showed targeted immunomodulation without overt immunosuppression.
- CD14 was identified as a key regulator of macrophage response to heart injury.

## Abstract

•This series of randomized and blinded preclinical trials is the first to investigate a clinically practicable CD14 blockade strategy initiated at reperfusion in a translational model of STEMI with key clinical features.•Anti-CD14 antibody therapy with a murine analogue of atibuclimab mitigated post-acute progression of left ventricular dysfunction, dilatation and hemodynamic decompensation over 28 days, assessed by multiple translational modalities (including echocardiography, cardiac magnetic resonance, and invasive intracardiac pressure-volume catheterization).•Integrative multiomic analyses revealed early targeted immunomodulation of the monocyte/macrophage without overt immunosuppression, proposing CD14 as a master regulator of the monocyte/macrophage response to acute myocardial injury.•These data inform and support future fundamental and clinical research into CD14 blockade strategies, particularly in the setting of STEMI.

This series of randomized and blinded preclinical trials is the first to investigate a clinically practicable CD14 blockade strategy initiated at reperfusion in a translational model of STEMI with key clinical features.

Anti-CD14 antibody therapy with a murine analogue of atibuclimab mitigated post-acute progression of left ventricular dysfunction, dilatation and hemodynamic decompensation over 28 days, assessed by multiple translational modalities (including echocardiography, cardiac magnetic resonance, and invasive intracardiac pressure-volume catheterization).

Integrative multiomic analyses revealed early targeted immunomodulation of the monocyte/macrophage without overt immunosuppression, proposing CD14 as a master regulator of the monocyte/macrophage response to acute myocardial injury.

These data inform and support future fundamental and clinical research into CD14 blockade strategies, particularly in the setting of STEMI.

These preclinical trials provide the first evidence of cluster of differentiation 14 (CD14) blockade with a murine analogue of atibuclimab, a CD14-neutralizing antibody, preventing secondary immunological exacerbation of cardiac injury in a translational mouse model of reperfused ST-segment elevation myocardial infarction (STEMI), assessed using multiple clinical modalities. Multiomic studies suggest CD14 blockade downregulated macrophage-specific proinflammatory and tissue-wide remodeling processes without suppression of monocyte-macrophage infiltration or repair. These findings support a clinically practicable targeted immunomodulatory strategy of CD14 blockade initiated at reperfusion to prevent chronic immunological progression toward ischemic heart failure, and provide new insights into the pleiotropic roles of CD14 in inflammation and myocardial injury.