STAT3 mutation-associated airway epithelial defects in Job syndrome - 03/08/23
Abstract |
Background |
Job syndrome is a disease of autosomal dominant hyper-IgE syndrome (AD-HIES). Patients harboring STAT3 mutation are particularly prone to airway remodeling and airway infections.
Objectives |
Airway epithelial cells play a central role as the first line of defense against pathogenic infection and express high levels of STAT3. This study thus interrogates how AD-HIES STAT3 mutations impact the physiological functions of airway epithelial cells.
Methods |
This study created human airway basal cells expressing 4 common AD-HIES STAT3 mutants (R382W, V463del, V637M, and Y657S). In addition, primary airway epithelial cells were isolated from a patient with Job syndrome who was harboring a STAT3-S560del mutation and from mice harboring a STAT3-V463del mutation. Cell proliferation, differentiation, barrier function, bacterial elimination, and innate immune responses to pathogenic infection were quantitatively analyzed.
Results |
STAT3 mutations reduce STAT3 protein phosphorylation, nuclear translocation, transcription activity, and protein stability in airway basal cells. As a consequence, STAT3-mutated airway basal cells give rise to airway epithelial cells with abnormal cellular composition and loss of coordinated mucociliary clearance. Notably, AD-HIES STAT3 airway epithelial cells are defective in bacterial killing and fail to initiate vigorous proinflammatory responses and neutrophil transepithelial migration in response to an experimental model of Pseudomonas aeruginosa infection.
Conclusions |
AD-HIES STAT3 mutations confer numerous abnormalities to airway epithelial cells in cell differentiation and host innate immunity, emphasizing their involvement in the pathogenesis of lung complications in Job syndrome. Therefore, therapies must address the epithelial defects as well as the previously noted immune cell defects to alleviate chronic infections in patients with Job syndrome.
Il testo completo di questo articolo è disponibile in PDF.Key words : AD-HIES STAT3 mutation, cell differentiation, mucociliary clearance, innate immunity, neutrophil chemotaxis
Abbreviations used : AD-HIES, MCT, μOCT, PAO1, WT
Mappa
| This work was supported by Job Research Foundation (H.M.), Cystic Fibrosis Foundation Research Grant (MOU19G0 [H.M.]), Hood Child Health Research Award (H.M.), Harvard Stem Cell Institute Seed Grant (SG-0120-19-00 [H.M.]), the National Institute of Allergy and Infectious Diseases (R01AI095338 [B.P.H.]; 5R01AI150181 J. M V.]), Massachusetts General Hospital Pathways Program Grants (M.B.F.), Massachusetts General Hospital Executive Committee on Research Fund for Medical Discovery (M.B.F.), National Institutes of Health–National Institute of Allergy and Infectious Diseases (T32HL116275 [M.B.F.]), the French National Research Agency (ANR) under the “Investments for the Future” program (ANR-10-IAHU-01 [A.P.]), the ANR-Food and Nutrition Service (FNS) LTh-MSMD-CMCD (ANR-18-CE93-0008-01 [A.P.]), The Rockefeller University, and the National Institutes of Health (R01AI127564 [A.P.]). |
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| Disclosure of potential conflict of interest: C. Tcherakian has received payments/honoraria from GSK, Astra Zeneca, Sanofi, Chiesi, and Boehringer. F. Danion has received payments/honoraria from Gilead and Pfizer. H. Salvator has received payments/honoraria from Oxyvie. L-J. Couderc has received financial support from Novartis, LVL Médical Groupe, and ARIA Medical. C. Givel has received payments/honoraria from Epione (Isis Medical). M.B. Feldman is currently working for and holds stock and options in Vertex Pharmaceuticals Inc. G.J. Tearney has received sponsored research funding from Wayvector, Verdure, AstraZeneca, and Xsphera Biosciences; and has a financial/fiduciary interest in SpectraWave. The rest of the authors declare that they have no relevant conflicts of interest. |
Vol 152 - N° 2
P. 538-550 - agosto 2023 Ritorno al numero
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