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Corrigendum Open Access | 10.1172/JCI183441

NFĸB signaling drives myocardial injury via CCR2+ macrophages in a preclinical model of arrhythmogenic cardiomyopathy

Stephen P. Chelko, Vinay R. Penna, Morgan Engel, Emily A. Shiel, Ann M. Centner, Waleed Farra, Elisa N. Cannon, Maicon Landim-Vieira, Niccole Schaible, Kory Lavine, and Jeffrey E. Saffitz

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Published July 1, 2024 - More info

Published in Volume 134, Issue 13 on July 1, 2024
J Clin Invest. 2024;134(13):e183441. https://doi.org/10.1172/JCI183441.
© 2024 Chelko et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published July 1, 2024 - Version history
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NFĸB signaling drives myocardial injury via CCR2+ macrophages in a preclinical model of arrhythmogenic cardiomyopathy
Stephen P. Chelko, … , Kory Lavine, Jeffrey E. Saffitz
Stephen P. Chelko, … , Kory Lavine, Jeffrey E. Saffitz
A therapeutically targetable innate immune mechanism regulates myocardial injury and cardiac function in a clinically relevant mouse model of arrhythmogenic cardiomyopathy.
Research Article Cardiology Immunology

NFĸB signaling drives myocardial injury via CCR2+ macrophages in a preclinical model of arrhythmogenic cardiomyopathy

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Abstract

Nuclear factor κ-B (NFκB) is activated in iPSC-cardiac myocytes from patients with arrhythmogenic cardiomyopathy (ACM) under basal conditions, and inhibition of NFκB signaling prevents disease in Dsg2mut/mut mice, a robust mouse model of ACM. Here, we used genetic approaches and single-cell RNA-Seq to define the contributions of immune signaling in cardiac myocytes and macrophages in the natural progression of ACM using Dsg2mut/mut mice. We found that NFκB signaling in cardiac myocytes drives myocardial injury, contractile dysfunction, and arrhythmias in Dsg2mut/mut mice. NFκB signaling in cardiac myocytes mobilizes macrophages expressing C-C motif chemokine receptor-2 (CCR2+ cells) to affected areas within the heart, where they mediate myocardial injury and arrhythmias. Contractile dysfunction in Dsg2mut/mut mice is caused both by loss of heart muscle and negative inotropic effects of inflammation in viable muscle. Single nucleus RNA-Seq and cellular indexing of transcriptomes and epitomes (CITE-Seq) studies revealed marked proinflammatory changes in gene expression and the cellular landscape in hearts of Dsg2mut/mut mice involving cardiac myocytes, fibroblasts, and CCR2+ macrophages. Changes in gene expression in cardiac myocytes and fibroblasts in Dsg2mut/mut mice were dependent on CCR2+ macrophage recruitment to the heart. These results highlight complex mechanisms of immune injury and regulatory crosstalk between cardiac myocytes, inflammatory cells, and fibroblasts in the pathogenesis of ACM.

Authors

Stephen P. Chelko, Vinay R. Penna, Morgan Engel, Emily A. Shiel, Ann M. Centner, Waleed Farra, Elisa N. Cannon, Maicon Landim-Vieira, Niccole Schaible, Kory Lavine, Jeffrey E. Saffitz

×

Original citation: J Clin Invest. 2024;134(10):e172014. https://doi.org/10.1172/JCI172014

Citation for this corrigendum: J Clin Invest. 2024;134(13):e183441. https://doi.org/10.1172/JCI183441

The authors recently became aware that in Figure 8E of the original article, the left and right graphs were duplicates. The correct data were provided in the original supporting data values file. The HTML and PDF versions of the article have been updated. The corrected figure appears below:

The authors regret the error.

Footnotes

See the related article at NFĸB signaling drives myocardial injury via CCR2+ macrophages in a preclinical model of arrhythmogenic cardiomyopathy.

Version history
  • Version 1 (July 1, 2024): Electronic publication

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