{"doi":"10.1016/j.jaci.2025.09.023","title":"Effects of type 3 and neutrophilic inflammation on type 2 chronic rhinosinusitis with nasal polyps","abstract":"BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) is most commonly divided into 3 endotypes (type 1 [T1], T2, and T3) on the basis of the T-cell cytokine profiles. Although neutrophils are classically associated with T3 inflammation in chronic rhinosinusitis, neutrophilic infiltration can be present without a T3 signal. OBJECTIVE: We sought to identify the effects of T3 and neutrophilic (called neutrophil variant or Vneut) inflammation on clinical presentations and phenotype-associated mechanisms in patients with T2 CRSwNP. METHODS: We obtained 66 control ethmoid tissues and 158 nasal polyps (NPs). We measured mRNA markers for T1, T2, T3, and Vneut inflammation by quantitative RT-PCR and whole RNA expression profiles by bulk RNA sequencing. We investigated associations between the endotypes and natural histories and predicted molecular pathways by gene enrichment analysis. RESULTS: Because 96% of the NPs had T2 endotype, most T1, T3, and Vneut inflammation coexisted with T2 endotype. Recurrent NP was associated with mixed T2 + T3 (P = .012) as well as T2 + Vneut (P = .022) inflammation, whereas sinus computed tomography and NP scores were associated only with T2 + Vneut inflammation (P < .05). Compared with control tissues, we identified shared and specific dysregulated genes in T2 single, T2 + T3, and T2 + Vneut mixed endotypes, and the results suggest that NP recurrence (T2 + T3 and T2 + Vneut shared dysregulated genes) was associated with activation of cytotoxic T cells and M1 macrophages, whereas sinus computed tomography and NP scores (T2 + Vneut-specific genes) were associated with activation of neutrophils, M2 macrophages, and fibroblasts as well as with downregulation of innate host defense. CONCLUSIONS: T3 and neutrophilic inflammation induce different molecular pathways resulting in distinct clinical presentations in T2 CRSwNP.","journal":"Journal of Allergy and Clinical Immunology","year":2025,"id":547598,"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":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9696,"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":656019,"name":"Aiko I. Klingler","orcid":null,"position":1,"is_corresponding":false},{"id":1213186,"name":"Masanori Kidoguchi","orcid":"0000-0002-2599-4780","position":2,"is_corresponding":false},{"id":656018,"name":"Julie A. Poposki","orcid":null,"position":3,"is_corresponding":false},{"id":656020,"name":"Lydia Suh","orcid":null,"position":4,"is_corresponding":false},{"id":848058,"name":"Junqin Bai","orcid":"0000-0001-6012-2809","position":5,"is_corresponding":false},{"id":233265,"name":"Whitney W. Stevens","orcid":"0000-0002-2608-6610","position":6,"is_corresponding":false},{"id":233266,"name":"Anju T. Peters","orcid":"0000-0003-0745-2379","position":7,"is_corresponding":false},{"id":233260,"name":"Leslie C. Grammer","orcid":"0000-0001-6860-2014","position":8,"is_corresponding":false},{"id":480725,"name":"Kevin C. Welch","orcid":"0000-0003-4863-7206","position":9,"is_corresponding":false},{"id":520504,"name":"Stephanie S. Smith","orcid":"0000-0002-0605-3993","position":10,"is_corresponding":false},{"id":480724,"name":"David B. Conley","orcid":"0000-0002-2611-6795","position":11,"is_corresponding":false},{"id":794945,"name":"Brian S. Schwartz","orcid":"0000-0002-0739-9865","position":12,"is_corresponding":false},{"id":392933,"name":"Micah Johnson","orcid":"0000-0001-6625-2719","position":13,"is_corresponding":false},{"id":841931,"name":"Amr Radwan","orcid":"0000-0003-1658-5229","position":14,"is_corresponding":false},{"id":233264,"name":"Robert P. Schleimer","orcid":"0000-0002-8330-0097","position":15,"is_corresponding":false},{"id":386199,"name":"Robert C. Kern","orcid":"0000-0002-8995-9175","position":16,"is_corresponding":false},{"id":348700,"name":"Bruce K. Tan","orcid":"0000-0001-9210-5050","position":17,"is_corresponding":false},{"id":921803,"name":"Shigeharu Fujieda","orcid":"0000-0002-9460-7377","position":18,"is_corresponding":false},{"id":1387046,"name":"Mitsuhiro Okano","orcid":"0000-0002-4275-5781","position":19,"is_corresponding":false},{"id":262060,"name":"Atsushi Kato","orcid":"0000-0001-9144-3138","position":20,"is_corresponding":false},{"id":1213185,"name":"Aiko Oka","orcid":"0000-0002-3648-2879","position":0,"is_corresponding":true}],"reference_count":65,"raw_metadata":null,"created_at":"2026-07-19T02:53:41.314800Z","pmid":"41067280","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":[]}