{"doi":"10.1172/jci172014","title":"NFĸB signaling drives myocardial injury via CCR2+ macrophages in a preclinical model of arrhythmogenic cardiomyopathy","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.","journal":"Journal of Clinical Investigation","year":2024,"id":421869,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":28,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9528,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":552523,"name":"Vinay Penna","orcid":"0000-0002-9082-7874","position":1,"is_corresponding":false},{"id":1044734,"name":"Morgan Engel","orcid":null,"position":2,"is_corresponding":false},{"id":567369,"name":"Emily Shiel","orcid":"0009-0009-6491-4331","position":3,"is_corresponding":false},{"id":1214877,"name":"Ann M. Centner","orcid":"0000-0002-9742-5165","position":4,"is_corresponding":false},{"id":1215386,"name":"Waleed Farra","orcid":null,"position":5,"is_corresponding":false},{"id":363203,"name":"Elisa N. Cannon","orcid":null,"position":6,"is_corresponding":false},{"id":642878,"name":"Maicon Landim-Vieira","orcid":"0000-0002-6696-8888","position":7,"is_corresponding":false},{"id":1045574,"name":"Niccole Schaible","orcid":"0000-0002-4765-5966","position":8,"is_corresponding":false},{"id":247530,"name":"Kory J. Lavine","orcid":"0000-0003-1948-9945","position":9,"is_corresponding":false},{"id":640146,"name":"Jeffrey E. Saffitz","orcid":"0000-0001-8568-9457","position":10,"is_corresponding":false},{"id":492572,"name":"Stephen P. Chelko","orcid":"0000-0003-1675-5945","position":0,"is_corresponding":true}],"reference_count":44,"raw_metadata":null,"created_at":"2026-07-19T01:57:41.370244Z","pmid":"38564300","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}