STAT3 mutation-associated airway epithelial defects in Job syndrome - 03/08/23

Doi : 10.1016/j.jaci.2022.12.821

Yihan Zhang, PhD ^a,^b,^r, Tian Lin, PhD ^a,^b,^r, Hui Min Leung, PhD ^c,^d, Cheng Zhang, PhD ^e, Brittany Wilson-Mifsud, MS ^a,^b,^r, Michael B. Feldman, PhD, MD ^g,^q, Anne Puel, MD ^g,^h,ⁱ, Fanny Lanternier, PhD, MD ^j,^k, Louis-Jean Couderc, MD ^l,^m, Francois Danion, PhD, MD ^n,^o, Emilie Catherinot, MD ^l, Hélène Salvator, MD ^l,^m, Colas Tcherkian, MD ^l, Claire Givel, MD ^l,^m, Jie Xu, PhD ^p, Guillermo J. Tearney, PhD, MD ^c,^d, Jatin M. Vyas, PhD, MD ^f,^q, Hu Li, PhD ^e, Bryan P. Hurley, PhD ^a,^b,^r, Hongmei Mou, PhD ^a,^b,^r,^⁎
^a Mucosal Immunology and Biology Research Center, Massachusetts General Hospital, Boston, Mass
^c Wellman Center for Photomedicine, Massachusetts General Hospital, and the Departments of Pediatrics, Harvard Medical School, Boston, Mass
^d Department of Pathology, Massachusetts General Hospital, Boston, Mass
^f Division of Pulmonary and Critical Care Medicine, Massachusetts General Hospital, Boston, Mass
^r Division of Pediatric Pulmonary Medicine, Massachusetts General Hospital for Children, Boston, Mass
^b Departments of Pediatrics, Harvard Medical School, Boston, Mass
^q Departments of Medicine, Harvard Medical School, Boston, Mass
^e Center for Individualized Medicine, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minn
^g Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherché (INSERM) U1163, Paris, France
^h University of Paris, Imagine Institute, Paris, France
^j Institut Pasteur, Université Paris Cité, Centre National de Référence des Mycoses Invasives et Antifongiques, Centre National de la Recherche Scientifique, Unite Mixté de Recherche (UMR) 2000, Paris, France
^k Service de Maladies Infectieuses, Hôpital Necker, Assistance Publique–Hôpitaux de Paris, Paris, France
^m Laboratoire Virologie et Immunologie Moléculaires Suresnes, UMR 0892 Paris-Saclay University, Paris, France
ⁱ St. Giles Laboratory of Human Genetics of Infectious Diseases, The Rockefeller University, New York, NY
^l Respiratory Diseases Department, Foch Hospital, Suresnes, France
ⁿ Department of Infectious Diseases, Centre Hospitalier Universitaire de Strasbourg, Strasbourg, France
^o Laboratoire d'ImmunoRhumatologie Moléculaire, INSERM UMR_S 1109, Université de Strasbourg, Strasbourg, France
^p Center for Advanced Models for Translational Sciences and Therapeutics, University of Michigan Medical Center, University of Michigan Medical School, Ann Arbor, Mich

^∗Corresponding author: Hongmei Mou, PhD, The Mucosal Immunology and Biology Research Center, Massachusetts General Hospital, 55 Fruit Street, Jackson 1402, Boston, MA 02114, USA.The Mucosal Immunology and Biology Research CenterMassachusetts General Hospital55 Fruit StreetJackson 1402BostonMA02114USA

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.

Le texte complet de cet article est disponible en PDF.

Key words : AD-HIES STAT3 mutation, cell differentiation, mucociliary clearance, innate immunity, neutrophil chemotaxis

Abbreviations used : AD-HIES, MCT, μOCT, PAO1, WT

Plan

Methods

Results

AD-HIES STAT3 mutations result in the loss of function of STAT3 signaling activity in human airway basal cells

AD-HIES STAT3 airway epithelial cells have the deranged cellular composition, impaired mucociliary clearance, and decreased bacterial killing

AD-HIES STAT3 epithelial cells fail to mount robust inflammatory responses to pathogenic infection

Airway epithelial cells isolated from a patient and a mouse with Job syndrome exhibit similar defects in cell differentiation, mucociliary clearance, and innate immunity

Discussion

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.]).

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.

Export

Vol 152 - N° 2

P. 538-550 - août 2023 Retour au numéro

Article précédent

The efficacy and safety of systemic corticosteroids as first line treatment for granulomatous lymphocytic interstitial lung disease
Bas Smits, Sigune Goldacker, Suranjith Seneviratne, Marion Malphettes, Hilary Longhurst, Omar E. Mohamed, Carla Witt-Rautenberg, Lucy Leeman, Eva Schwaneck, Isabelle Raymond, Kilifa Meghit, Annette Uhlmann, Christine Winterhalter, Joris van Montfrans, Marion Klima, Sarita Workman, Claire Fieschi, Lorena Lorenzo, Sonja Boyle, Shamin Onyango-Odera, Suzanne Price, Marc Schmalzing, Valerie Aurillac, Antje Prasse, Ieneke Hartmann, Jennifer J. Meerburg, Mariette Kemner-van de Corput, Harm Tiddens, Bodo Grimbacher, Peter Kelleher, Smita Y. Patel, Anne-Sophie Korganow, Jean-Francois Viallard, Hans-Peter Tony, Claire Bethune, Hendrik Schulze-Koops, Torsten Witte, Aarnoud Huissoon, Helen Baxendale, Sofia Grigoriadou, Eric Oksenhendler, Siobhan O. Burns, Klaus Warnatz

Bienvenue sur EM-consulte, la référence des professionnels de santé.
L’accès au texte intégral de cet article nécessite un abonnement.

Déjà abonné à cette revue ?

connectez-vous ou créez un compte

STAT3 mutation-associated airway epithelial defects in Job syndrome - 03/08/23

Abstract

Background

Objectives

Methods

Results

Conclusions

Plan

Export citations

Fichier

Contenu

Accès rapides

Mon compte

Aide & support

Plateformes Elsevier Masson

Déclaration CNIL