{"doi":"10.1164/rccm.202211-2096oc","title":"Cystic Fibrosis Reprograms Airway Epithelial IL-33 Release and Licenses IL-33–Dependent Inflammation","abstract":"Abstract Rationale Type 2 inflammation has been described in people with cystic fibrosis (CF). Whether loss of CFTR (cystic fibrosis transmembrane conductance regulator) function contributes directly to a type 2 inflammatory response has not been fully defined. Objectives The potent alarmin IL-33 has emerged as a critical regulator of type 2 inflammation. We tested the hypothesis that CFTR deficiency increases IL-33 expression and/or release and deletion of IL-33 reduces allergen-induced inflammation in the CF lung. Methods Human airway epithelial cells (AECs) grown from non-CF and CF cell lines and Cftr +/+ and Cftr −/− mice were used in this study. Pulmonary inflammation in Cftr +/+ and Cftr −/− mice with and without IL-33 or ST2 (IL-1 receptor-like 1) germline deletion was determined by histological analysis, BAL, and cytokine analysis. Measurements and Main Results After allergen challenge, both CF human AECs and Cftr −/− mice had increased IL-33 expression compared with control AECs and Cftr +/+ mice, respectively. DUOX1 (dual oxidase 1) expression was increased in CF human AECs and Cftr −/− mouse lungs compared with control AECs and lungs from Cftr +/+ mice and was necessary for the increased IL-33 release in Cftr −/− mice compared with Cftr +/+ mice. IL-33 stimulation of Cftr −/− CD4+ T cells resulted in increased type 2 cytokine production compared with Cftr+/+ CD4+ T cells. Deletion of IL-33 or ST2 decreased both type 2 inflammation and neutrophil recruitment in Cftr −/− mice compared with Cftr +/+ mice. Conclusions Absence of CFTR reprograms airway epithelial IL-33 release and licenses IL-33–dependent inflammation. Modulation of the IL-33/ST2 axis represents a novel therapeutic target in CF type 2–high and neutrophilic inflammation.","journal":"American Journal of Respiratory and Critical Care Medicine","year":2023,"id":332676,"datarank":0.4887144807032224,"base_score":3.258096538021482,"endowment":3.258096538021482,"self_citation_contribution":0.4887144807032224,"citation_network_contribution":0.0,"self_endowment_contribution":0.4887144807032224,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":25,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9463,"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":924041,"name":"Christopher M. Thomas","orcid":"0000-0002-2810-0455","position":1,"is_corresponding":false},{"id":805169,"name":"Ashley Y. Wu","orcid":"0000-0001-6526-9973","position":2,"is_corresponding":false},{"id":1059907,"name":"Mark Rusznak","orcid":null,"position":3,"is_corresponding":false},{"id":1059310,"name":"Jian Zhang","orcid":"0000-0001-5552-0132","position":4,"is_corresponding":false},{"id":715524,"name":"Weisong Zhou","orcid":"0000-0002-4419-2302","position":5,"is_corresponding":false},{"id":700666,"name":"Jacqueline-Yvonne Cephus","orcid":"0000-0002-4691-4014","position":6,"is_corresponding":false},{"id":456168,"name":"Katherine N. Gibson‐Corley","orcid":"0000-0002-1846-1580","position":7,"is_corresponding":false},{"id":532485,"name":"Vasiliy V. Polosukhin","orcid":null,"position":8,"is_corresponding":false},{"id":290002,"name":"Allison E. Norlander","orcid":"0000-0002-9357-485X","position":9,"is_corresponding":false},{"id":289419,"name":"Dawn C. Newcomb","orcid":"0000-0003-2592-9433","position":10,"is_corresponding":false},{"id":465072,"name":"David A. Stoltz","orcid":"0000-0003-0893-9015","position":11,"is_corresponding":false},{"id":290007,"name":"R. Stokes Peebles","orcid":"0000-0002-1429-7875","position":12,"is_corresponding":false},{"id":753628,"name":"Daniel P. Cook","orcid":"0000-0002-1152-4454","position":0,"is_corresponding":true}],"reference_count":50,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T01:09:35.125543Z","pmid":"36952660","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":[]}