{"doi":"10.1016/j.mucimm.2024.09.006","title":"CSF1-dependent macrophage support matrisome and epithelial stress-induced keratin remodeling in Eosinophilic esophagitis","abstract":"Atopic diseases such as Eosinophilic Esophagitis (EoE) often progress into fibrosis (FS-EoE), compromising organ function with limited targeted treatment options. Mechanistic understanding of FS-EoE progression is confounded by the lack of preclinical models and the heavy focus of research on eosinophils themselves. We found that macrophage accumulation precedes esophageal fibrosis in FS-EoE patients. We developed a FS-EoE model via chronic administration of oxazalone allergen, in a transgenic mouse over-expressing esophageal epithelial hIL-5 ( L2-IL5 OXA ). These mice display striking histopathologic features congruent with that found in FS-EoE patients. Unbiased proteomic analysis, using a unique extracellular-matrix (ECM) focused technique, identified an inflammation-reactive provisional basal lamina membrane signature and this was validated in two independent EoE patient RNA-sequencing/proteomic cohorts, supporting model significance. A wound healing signature was also observed involving hemostasis-associated molecules previously unnoted in EoE. We further identified the ECM glycoprotein, Tenascin-C (TNC), and the stress-responsive keratin-16 (KRT16) as IL-4 and IL-13 responsive mediators, acting as biomarkers of FS-EoE. To mechanistically address how the immune infiltrate shapes FS-EoE progression, we phenotyped the major immune cell subsets that coalesce with fibrosis in both the L2-IL5 OXA mice and in FS-EoE patients. We found that macrophage are required for matrisome and cytoskeletal remodeling. Importantly, we show that macrophage accumulation precedes esophageal fibrosis and provide a novel therapeutic target in FS-EoE as their depletion with anti-CSF1 attenuated reactive matrisome and cytoskeletal changes. Thus, macrophage-based treatments and the exploration of TNC and KRT16 as biomarkers may provide novel therapeutic options for patients with fibrostenosis.","journal":"Mucosal Immunology","year":2024,"id":469326,"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":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9523,"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":1088628,"name":"Gary E. Markey","orcid":"0000-0002-0698-3824","position":1,"is_corresponding":false},{"id":1303067,"name":"Juliet A Hammer","orcid":null,"position":2,"is_corresponding":false},{"id":1303068,"name":"Luke Simerly","orcid":null,"position":3,"is_corresponding":false},{"id":438368,"name":"Monika Dzieciątkowska","orcid":"0000-0002-9947-2520","position":4,"is_corresponding":false},{"id":10990,"name":"Kimberly R. Jordan","orcid":"0000-0001-8380-7157","position":5,"is_corresponding":false},{"id":663126,"name":"Kelley E. Capocelli","orcid":"0000-0002-8256-2896","position":6,"is_corresponding":false},{"id":1302673,"name":"Kathleen Scullion","orcid":"0000-0002-2867-0108","position":7,"is_corresponding":false},{"id":1075919,"name":"Louise Crowe","orcid":"0000-0003-4619-9708","position":8,"is_corresponding":false},{"id":1088629,"name":"Sinéad Ryan","orcid":"0000-0003-3397-1818","position":9,"is_corresponding":false},{"id":985833,"name":"Jennifer O. Black","orcid":"0000-0002-2181-9344","position":10,"is_corresponding":false},{"id":353838,"name":"Taylor Crue","orcid":"0000-0002-8469-9546","position":11,"is_corresponding":false},{"id":664063,"name":"Rachel Andrews","orcid":null,"position":12,"is_corresponding":false},{"id":663131,"name":"Cassandra Burger","orcid":"0000-0002-6850-7700","position":13,"is_corresponding":false},{"id":459304,"name":"Eóin N. McNamee","orcid":"0000-0002-3331-3148","position":14,"is_corresponding":false},{"id":233046,"name":"Glenn T. Furuta","orcid":"0000-0003-3262-3571","position":15,"is_corresponding":false},{"id":663135,"name":"Calies Menard‐Katcher","orcid":"0000-0003-2810-8171","position":16,"is_corresponding":false},{"id":689425,"name":"Joanne C. Masterson","orcid":"0000-0002-8336-9879","position":17,"is_corresponding":false},{"id":1303066,"name":"Taylor M Benson","orcid":null,"position":0,"is_corresponding":true}],"reference_count":70,"raw_metadata":null,"created_at":"2026-07-19T02:05:28.027781Z","pmid":"39343055","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":[]}