{"doi":"10.1016/j.ajt.2023.10.020","title":"Human leukocyte antigen class I antibody-activated endothelium promotes CD206+ M2 macrophage polarization and MMP9 secretion through TLR4 signaling and P-selectin in a model of antibody-mediated rejection and allograft vasculopathy","abstract":"HLA donor-specific antibodies (DSA) elicit alloimmune responses against the graft vasculature, leading to endothelial cell (EC) activation and monocyte infiltration during antibody-mediated rejection (AMR). AMR promotes chronic inflammation and remodeling, leading to thickening of the arterial intima termed transplant vasculopathy or cardiac allograft vasculopathy (CAV) in heart transplants. Intragraft-recipient macrophages serve as a diagnostic marker in AMR; however, their polarization and function remain unclear. In this study, we utilized an in vitro Transwell coculture system to explore the mechanisms of monocyte-to-macrophage polarization induced by HLA I DSA-activated ECs. Anti-HLA I (IgG or F(ab') 2 ) antibody-activated ECs induced the polarization of M2 macrophages with increased CD206 expression and MMP9 secretion. However, inhibition of TLR4 signaling or PSGL-1-P-selectin interactions significantly decreased both CD206 and MMP9. Monocyte adherence to Fc-P-selectin coated plates induced M2 macrophages with increased CD206 and MMP9. Moreover, Fc-receptor and IgG interactions synergistically enhanced active-MMP9 in conjunction with P-selectin. Transcriptomic analysis of arteries from DSA+CAV+ rejected cardiac allografts and multiplex-immunofluorescent staining illustrated the expression of CD68+CD206+CD163+MMP9+ M2 macrophages within the neointima of CAV-affected lesions. These findings reveal a novel mechanism linking HLA I antibody-activated endothelium to the generation of M2 macrophages which secrete vascular remodeling proteins contributing to AMR and CAV pathogenesis.","journal":"American Journal of Transplantation","year":2023,"id":330123,"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":16,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9582,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1042588,"name":"Yiping Jin","orcid":"0000-0001-6620-4274","position":1,"is_corresponding":false},{"id":705068,"name":"Harry Pickering","orcid":"0000-0003-2348-5410","position":2,"is_corresponding":false},{"id":705070,"name":"Rajesh Parmar","orcid":"0000-0002-6122-4345","position":3,"is_corresponding":false},{"id":919866,"name":"Nicole M. Valenzuela","orcid":"0000-0003-2024-5382","position":4,"is_corresponding":false},{"id":325148,"name":"Rebecca A. Sosa","orcid":"0000-0002-9860-6830","position":5,"is_corresponding":false},{"id":768040,"name":"Sebastiaan Heidt","orcid":"0000-0002-6700-188X","position":6,"is_corresponding":false},{"id":253658,"name":"Gregory A. Fishbein","orcid":"0000-0002-3632-5654","position":7,"is_corresponding":false},{"id":405221,"name":"Enrique Rozengurt","orcid":"0000-0002-7838-9170","position":8,"is_corresponding":false},{"id":278887,"name":"William M. Baldwin","orcid":"0000-0002-7271-1827","position":9,"is_corresponding":false},{"id":72293,"name":"Robert L. Fairchild","orcid":"0000-0002-7107-5259","position":10,"is_corresponding":false},{"id":1054382,"name":"Elaine F Reed","orcid":null,"position":11,"is_corresponding":false},{"id":1042587,"name":"Jessica Nevarez‐Mejia","orcid":"0000-0003-3390-4818","position":0,"is_corresponding":true}],"reference_count":71,"raw_metadata":null,"created_at":"2026-07-19T01:09:10.120703Z","pmid":"38379280","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":[]}