{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T09:46:36Z","timestamp":1785750396272,"version":"3.56.0"},"reference-count":109,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2025,3,14]],"date-time":"2025-03-14T00:00:00Z","timestamp":1741910400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Research Ireland","award":["22\/FFP-P\/11470"],"award-info":[{"award-number":["22\/FFP-P\/11470"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Cystic Fibrosis (CF) is a life-shortening, multi-organ disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. Prominent clinical features of CF take place in the lung, hallmarked by cycles of bacterial infection and a dysfunctional inflammatory airway response, leading to eventual respiratory failure. Bidirectional crosstalk between epithelial cells, leukocytes (e.g., neutrophils, macrophages) and bacteria via release of intra-cellular mediators is key to driving inflammation in CF airways. In recent years, a highly effective combination of therapeutics targeting the CFTR defect have revolutionized treatment in CF. Despite these advancements and due to the complexity of the immune response in the CF airway, the full impact of highly effective modulator therapy (HEMT) on airway inflammation is not fully determined. This review provides the evidence to date on crosstalk mechanisms between host epithelium, leukocytes and bacteria and examines the effect of HEMT on both soluble and membrane-derived immune mediators in clinical samples. The varied effects of HEMT on expression of key proteases, cytokines and extracellular vesicles (EVs) in relation to clinical parameters is assessed. Advances in treatment with HEMT have shown potential in dampening the chronic inflammatory response in CF airways. However, to fully quell inflammation and maximize lung tissue resilience, further interventions may be necessary. Exploring the effects of HEMT on key immune mediators paves the way for identifying new anti-inflammatory approaches targeting host immune cell interactions, such as EV-directed lung therapies.<\/jats:p>","DOI":"10.3390\/ijms26062636","type":"journal-article","created":{"date-parts":[[2025,3,14]],"date-time":"2025-03-14T13:07:51Z","timestamp":1741957671000},"page":"2636","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Innate Immunity in Cystic Fibrosis: Varied Effects of CFTR Modulator Therapy on Cell-to-Cell Communication"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-2778-3459","authenticated-orcid":false,"given":"Jennifer","family":"Hynes","sequence":"first","affiliation":[{"name":"School of Pharmacy and Biomolecular Sciences, RCSI University of Medicine and Health Sciences, D02 YN77 Dublin, Ireland"},{"name":"Children\u2019s Health Ireland Translational Research Centre, Children\u2019s Health Ireland at Crumlin, D12 N512 Dublin, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clifford C.","family":"Taggart","sequence":"additional","affiliation":[{"name":"Airway Innate Immunity Research (AiiR) Group, Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen\u2019s University Belfast, Belfast BT9 7BL, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3526-9985","authenticated-orcid":false,"given":"Rabindra","family":"Tirouvanziam","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Emory University, Atlanta, GA 30322, USA"},{"name":"Center for CF and Airways Disease Research, Children's Healthcare of Atlanta, Atlanta, GA 30322, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6813-9840","authenticated-orcid":false,"given":"Judith A.","family":"Coppinger","sequence":"additional","affiliation":[{"name":"School of Pharmacy and Biomolecular Sciences, RCSI University of Medicine and Health Sciences, D02 YN77 Dublin, Ireland"},{"name":"Children\u2019s Health Ireland Translational Research Centre, Children\u2019s Health Ireland at Crumlin, D12 N512 Dublin, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,3,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2519","DOI":"10.1016\/S0140-6736(16)00576-6","article-title":"Cystic Fibrosis","volume":"388","author":"Elborn","year":"2016","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"S39","DOI":"10.1002\/ppul.23242","article-title":"Inflammation and Its Genesis in Cystic Fibrosis","volume":"50","author":"Nichols","year":"2015","journal-title":"Pediatr. 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