{"doi":"10.1161/circulationaha.124.072411","title":"CD206 <sup>+</sup> IL-4Rα <sup>+</sup> Macrophages Are Drivers of Adverse Cardiac Remodeling in Ischemic Cardiomyopathy","abstract":"BACKGROUND: The role of cardiac CD (cluster of differentiation) 206 + macrophages in chronic heart failure (HF) is unknown. We examined whether CD206 + macrophages expressing IL (interleukin)–4Rα are key drivers of adverse left ventricular (LV) remodeling in HF. METHODS: Adult C57BL/6 mice underwent nonreperfused myocardial infarction to induce HF. Macrophages in murine and human hearts were profiled using flow cytometry and immunostaining. In vivo myeloid-specific IL-4Rα deletion and intramyocardial macrophage adoptive transfer defined the functional effects of macrophages polarized by IL-4 (M[IL-4]). Antisense oligonucleotides were used for in vivo IL-4Rα gene silencing in mice. RESULTS: CD206 + macrophages steadily expanded in hearts after myocardial infarction, such that at 8 weeks after myocardial infarction, they comprised ≈85% of all macrophages. These macrophages were proliferative, predominantly CCR2 – (C-C motif chemokine receptor) and MHC (major histocompatibility complex) II hi , and correlated with LV dysfunction and fibrosis. Nearly half of CD206 + macrophages expressed IL-4Rα, and the majority of CD206 + IL-4Rα + macrophages coexpressed profibrotic FIZZ (found in inflammatory zone) 1. Bone marrow–derived CD206 + M[IL-4] macrophages also exhibited marked upregulation of FIZZ1 and induced FIZZ1-dependent myofibroblast differentiation of both cardiac mesenchymal stem cells and cardiac fibroblasts, in part related to DLL (Delta-like ligand)-4/Jagged1-Notch1 signaling in cardiac mesenchymal stem cells. Intramyocardial adoptive transfer of M[IL-4], but not IL-10-polarized (M[IL-10]), CD206 + macrophages to naïve mice induced progressive LV remodeling over 4 weeks, increasing fibrosis, cardiomyocyte hypertrophy, and apoptosis. Myeloid-specific IL-4Rα gene deletion in HF (initiated 4 weeks after myocardial infarction) in IL-4Rα f/f LysM-Cre ERT2 mice significantly reduced CD206 + macrophage proliferation and effectively depleted CD206 + IL-4Rα + cardiac macrophages. This was associated with abrogation of LV remodeling progression, reduction of cardiac fibrosis, and improved neovascularization. In vivo IL-4Rα gene silencing in mice with established HF effectively depleted cardiac CD206 + IL-4Rα + macrophages and reversed LV remodeling, improving fibrosis, neovascularization, and dysfunction, and suppressed both local and systemic inflammation. Last, alternatively activated CD206 + and CD163 + macrophages were significantly expanded in human failing hearts and correlated with fibrosis. The majority of CD163 + macrophages expressed IL-4Rα and FIZZ3, the human homolog of FIZZ1. CONCLUSIONS: Cardiac CD206 + IL-4Rα + macrophages proliferate and expand in HF and are key mediators of pathological remodeling and fibrosis, in part through the secretion of FIZZ1. Inhibition of CD206 + macrophage IL-4Rα signaling alleviates LV remodeling in ischemic cardiomyopathy.","journal":"Circulation","year":2025,"id":510805,"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":18,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9617,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":442306,"name":"Mohamed Ameen Ismahil","orcid":"0000-0002-7452-6123","position":1,"is_corresponding":false},{"id":729501,"name":"Yujie Zhu","orcid":"0000-0002-4645-7669","position":2,"is_corresponding":false},{"id":885000,"name":"Gregg Rokosh","orcid":"0000-0002-9214-2254","position":3,"is_corresponding":false},{"id":442305,"name":"Tariq Hamid","orcid":"0000-0002-4588-3754","position":4,"is_corresponding":false},{"id":1337892,"name":"Guihua Zhou","orcid":"0009-0006-0251-7056","position":5,"is_corresponding":false},{"id":696311,"name":"Steven M. Pogwizd","orcid":"0000-0002-7596-853X","position":6,"is_corresponding":false},{"id":371996,"name":"Sumanth D. Prabhu","orcid":"0000-0002-7247-7241","position":7,"is_corresponding":false},{"id":746536,"name":"Qiongxin Wang","orcid":null,"position":0,"is_corresponding":true}],"reference_count":66,"raw_metadata":null,"created_at":"2026-07-19T02:47:50.575618Z","pmid":"40308203","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":[]}