CD14 Blockade Attenuates Arrhythmogenic Cardiomyopathy
- 1Washington University School of Medicine
Abstract
Background: Arrhythmogenic cardiomyopathy (ACM) is a genetic and phenotypically heterogeneous myocardial disorder characterized by progressive cardiomyocyte loss, immune cell infiltration, and fibro-fatty replacement of the ventricular myocardium, with an increased risk of sudden cardiac death (SCD), predominantly caused by mutations in cardiac desmosomal genes including PKP2, DSP, and DSG2. We previously described the pivotal role of NF{kappa}B and CCR2+ cardiac macrophage-triggered inflammation in ACM pathogenesis. Methods: WT or Dsg2mut/mut mice were treated with either isotype control or anti-CD14 antibody once a week for the described treatment period (4 or 8 weeks). At the end of the treatment period, disease characteristics were assessed by echocardiography, electrocardiography, histology, immunofluorescence, positron emission tomography (PET) imaging and single-cell transcriptomics. Results: Here, we demonstrate the efficacy of neutralizing CD14 signaling, an important mediator of inflammatory macrophage activation, in attenuating ACM disease in vivo. Additionally, we elucidate shifts in the cellular and transcriptomic landscapes that occur following anti-CD14 antibody treatment in a well-established mouse model of ACM and identify substantial reductions in inflammatory macrophage and pro-fibrotic fibroblast populations. Conclusion: This study provides evidence that blockade of CD14 can attenuate the ACM disease phenotype. It may do so by inhibiting macrophage-based activation and inflammation, while also altering the transcriptional state of other important cell types. Collectively, these findings suggest that CD14 inhibition may be an effective option for ACM, which should be explored in early-phase clinical studies.
Related
- Elimination of Epicardial Late Potentials by Endocardial Ablation in Arrhythmogenic Right Ventricular Cardiomyopathy
- Stable truncating mutations in plakophilin-2 induce arrhythmogenic cardiomyopathy-like phenotypes in adult zebrafish
- CD300a Blockade attenuates renal fibrosis by enhancing macrophage efferocytosis and neutrophil MMP9 production
- RANKL blockade attenuates MASH by remodeling the hepatic immune microenvironment
- Selective activation of tetrodotoxin-sensitive sodium channels by AaH-II drives arrhythmogenic late Na+ current in the heart
BibTeX
@misc{penna2026cd14,
title = {{CD14 Blockade Attenuates Arrhythmogenic Cardiomyopathy}},
author = {V. R. Penna and E. Ehle and W. Farra and E. N. Cannon and M. Landim-Vieira and A. M. Centner and M. C. Owen and R. Venkatesan and G. S. Heo and A. Das and Y. Liu and M. W. Appleby and D. Crowe and B. W. Ziegelaar and G. L. Redlich and J. E. Saffitz and S. P. Chelko and K. J. Lavine},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.30.755828},
url = {https://www.biorxiv.org/content/10.64898/2026.09.30.755828v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - CD14 Blockade Attenuates Arrhythmogenic Cardiomyopathy
AU - V. R. Penna
AU - E. Ehle
AU - W. Farra
AU - E. N. Cannon
AU - M. Landim-Vieira
AU - A. M. Centner
AU - M. C. Owen
AU - R. Venkatesan
AU - G. S. Heo
AU - A. Das
AU - Y. Liu
AU - M. W. Appleby
AU - D. Crowe
AU - B. W. Ziegelaar
AU - G. L. Redlich
AU - J. E. Saffitz
AU - S. P. Chelko
AU - K. J. Lavine
PY - 2026
DA - 2026/09/30
PB - bioRxiv
DO - 10.64898/2026.09.30.755828
UR - https://www.biorxiv.org/content/10.64898/2026.09.30.755828v1
AB - Background: Arrhythmogenic cardiomyopathy (ACM) is a genetic and phenotypically heterogeneous myocardial disorder characterized by progressive cardiomyocyte loss, immune cell infiltration, and fibro-fatty replacement of the ventricular myocardium, with an increased risk of sudden cardiac death (SCD), predominantly caused by mutations in cardiac desmosomal genes including PKP2, DSP, and DSG2. We previously described the pivotal role of NF{kappa}B and CCR2+ cardiac macrophage-triggered inflammation in ACM pathogenesis. Methods: WT or Dsg2mut/mut mice were treated with either isotype control or anti-CD14 antibody once a week for the described treatment period (4 or 8 weeks). At the end of the treatment period, disease characteristics were assessed by echocardiography, electrocardiography, histology, immunofluorescence, positron emission tomography (PET) imaging and single-cell transcriptomics. Results: Here, we demonstrate the efficacy of neutralizing CD14 signaling, an important mediator of inflammatory macrophage activation, in attenuating ACM disease in vivo. Additionally, we elucidate shifts in the cellular and transcriptomic landscapes that occur following anti-CD14 antibody treatment in a well-established mouse model of ACM and identify substantial reductions in inflammatory macrophage and pro-fibrotic fibroblast populations. Conclusion: This study provides evidence that blockade of CD14 can attenuate the ACM disease phenotype. It may do so by inhibiting macrophage-based activation and inflammation, while also altering the transcriptional state of other important cell types. Collectively, these findings suggest that CD14 inhibition may be an effective option for ACM, which should be explored in early-phase clinical studies.
ER -