Journal article
Cystic Fibrosis Reprograms Airway Epithelial IL-33 Release and Licenses IL-33 Dependent Inflammation
American journal of respiratory and critical care medicine, Vol.207(11), pp.1486-1497
06/01/2023
DOI: 10.1164/rccm.202211-2096OC
PMCID: PMC10263140
PMID: 36952660
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.
Details
- Title: Subtitle
- Cystic Fibrosis Reprograms Airway Epithelial IL-33 Release and Licenses IL-33 Dependent Inflammation
- Creators
- Daniel P CookChristopher M Thomas - Vanderbilt University Medical CenterAshley Y Wu - Vanderbilt University Medical CenterMark Rusznak - Vanderbilt University Medical CenterJian Zhang - Vanderbilt University Medical CenterWeisong Zhou - Vanderbilt University Medical CenterJacqueline-Yvonne Cephus - Vanderbilt University Medical CenterKatherine N Gibson-Corley - Vanderbilt University Medical CenterVasiliy V Polosukhin - Vanderbilt University Medical CenterAllison E Norlander - Vanderbilt University Medical CenterDawn C Newcomb - Vanderbilt University Medical CenterDavid A StoltzR. Stokes Peebles Jr - United States Department of Veterans Affairs
- Resource Type
- Journal article
- Publication Details
- American journal of respiratory and critical care medicine, Vol.207(11), pp.1486-1497
- DOI
- 10.1164/rccm.202211-2096OC
- PMID
- 36952660
- PMCID
- PMC10263140
- NLM abbreviation
- Am J Respir Crit Care Med
- ISSN
- 1073-449X
- eISSN
- 1535-4970
- Grant note
- DOI: 10.13039/100006492, name: Division of Intramural Research, National Institute of Allergy and Infectious Diseases, award: R01 AI 111820; DOI: 10.13039/100006492, name: U.S. Department of Veterans Affairs, award: 101BX004299; DOI: 10.13039/100006492, name: Cystic Fibrosis Foundation, award: COOK20L0; DOI: 10.13039/100006492, name: Division of Cancer Prevention, National Cancer Institute, award: 5P30 CA68485-19
- Language
- English
- Electronic publication date
- 03/23/2023
- Date published
- 06/01/2023
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Molecular Physiology and Biophysics; Pulmonary, Critical Care, and Occupational Medicine; The University of Iowa Institute for Vision Research; Internal Medicine
- Record Identifier
- 9984380461202771
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