{"doi":"10.1101/2021.09.26.461888","title":"Tuft cell-produced cysteinyl leukotrienes and IL-25 synergistically initiate lung type 2 inflammation","abstract":"ABSTRACT Aeroallergen sensing by airway epithelial cells can trigger pathogenic immune responses leading to chronic type 2 inflammation, the hallmark of airway diseases such as asthma. Airway tuft cells are specialized chemosensory epithelial cells and the dominant source of the epithelial cytokine IL-25 in the trachea and of cysteinyl leukotrienes (CysLTs) in the naïve murine nasal mucosa. The interaction of IL-25 and CysLTs and the contribution of tuft cell-derived CysLTs to the development of allergen-triggered inflammation in the airways has not been clarified. Here we show that inhalation of LTC 4 in combination with a subthreshold dose of IL-25 leads to dramatic synergistic induction of type 2 inflammation throughout the lungs, causing rapid eosinophilia, dendritic cell (DC) and inflammatory type 2 innate lymphoid cell (ILC2) expansion, and goblet cell metaplasia. While lung eosinophilia is dominantly mediated through the classical CysLT receptor CysLT 1 R, type 2 cytokines and activation of innate immune cells require signaling through both CysLT 1 R and CysLT 2 R. Tuft cell-specific deletion of the terminal enzyme requisite for CysLT production, Ltc4s , was sufficient to reduce both the innate immune response in the lung – eosinophilia, KLRG1 + ILC2 activation and DC recruitment – and the systemic immune response in the draining lymph nodes after inhalation of the mold aeroallergen Alternaria . Our findings identify surprisingly potent synergy of CysLTs and IL-25 downstream of aeroallergen-trigged activation of airway tuft cells leading to a highly polarized type 2 immune response and further implicate airway tuft cells as powerful modulators of type 2 immunity in the lungs. One Sentence Summary Tuft cells produce two highly synergistic mediators: LTC 4 and IL-25 to cooperatively induce allergen-driven airway inflammation.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2021,"id":216849,"datarank":0.3373290244069857,"base_score":1.6094379124341003,"endowment":1.6094379124341003,"self_citation_contribution":0.24141568686511508,"citation_network_contribution":0.09591333754187063,"self_endowment_contribution":0.24141568686511508,"citer_contribution":0.09591333754187063,"corpus_percentile":null,"corpus_rank":null,"citation_count":4,"citer_count":4,"citers_with_citation_signal":4,"citers_with_endowment":4,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9558,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":813221,"name":"Evan Lemire","orcid":"0000-0002-9490-7679","position":1,"is_corresponding":false},{"id":813222,"name":"Evelyn C. Avilés","orcid":"0000-0002-0448-487X","position":2,"is_corresponding":false},{"id":813223,"name":"Amelia Boyd","orcid":"0000-0002-3819-4395","position":3,"is_corresponding":false},{"id":813224,"name":"Caitlin Wong","orcid":"0000-0002-6807-7835","position":4,"is_corresponding":false},{"id":279506,"name":"Juying Lai","orcid":"0000-0002-2240-9806","position":5,"is_corresponding":false},{"id":731756,"name":"Tao Liu","orcid":"0000-0002-1182-991X","position":6,"is_corresponding":false},{"id":288514,"name":"Ichiro Matsumoto","orcid":"0000-0001-9987-7715","position":7,"is_corresponding":false},{"id":104340,"name":"Nora A. Barrett","orcid":"0000-0003-2211-8811","position":8,"is_corresponding":false},{"id":104339,"name":"Joshua A. Boyce","orcid":"0000-0002-2401-2351","position":9,"is_corresponding":false},{"id":3191,"name":"Adam L. Haber","orcid":"0000-0002-4229-2852","position":10,"is_corresponding":false},{"id":279507,"name":"Lora G. Bankova","orcid":"0000-0003-1141-1529","position":11,"is_corresponding":false},{"id":634341,"name":"Saltanat Ualiyeva","orcid":"0000-0002-2899-1366","position":0,"is_corresponding":true}],"reference_count":70,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-18T23:53:15.868165Z","pmid":null,"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":[]}