STAT3-Dependent Regulation of CFTR and Ciliogenesis Is Essential for Mucociliary Clearance and Innate Airway Defense in Hyper-IgE Syndrome

<b>Rationale:</b> Hyper-IgE syndrome (STAT3-HIES), also known as Job's syndrome, is a rare immunodeficiency disease typically caused by dominant-negative STAT3 mutations. STAT3-HIES is characterized by chronic pulmonary infection and inflammation, suggesting impaired innate host defense. <b>Objectives:</b> To identify airway epithelial host defense defects caused by STAT3 mutations that, together with immune dysfunction, contribute to recurrent pulmonary infections in STAT3-HIES. <b>Methods:</b> STAT3-HIES sputum was analyzed for biochemical and biophysical properties. STAT3-HIES excised lungs were harvested for histology, and bronchial brush samples were collected for RNA sequencing and <i>in vitro</i> culture. A STAT3-HIES-specific R382W mutation, expressed via lentivirus, and STAT3 knockout (CRISPR/Cas9) were studied in normal human bronchial epithelial cells under basal or inflammatory (IL1β)-stimulated conditions. Effects of STAT3 deficiency on transcriptomics, epithelial ion channel, secretory, antimicrobial, and ciliary functions were assessed. <b>Measurements and Main Results:</b> STAT3-HIES sputum showed increased mucus concentration and viscoelasticity. STAT3-HIES excised lungs exhibited mucus obstruction and elevated IL1β expression. STAT3 mutations reduced CFTR mRNA and protein amounts, impaired CFTR-dependent fluid and mucin secretion, suppressed antimicrobial peptide, cytokine, and chemokine expression, and acidified airway surface liquid at baseline and after IL1β exposure. Notably, mutant STAT3 suppressed IL1R1 expression. Furthermore, STAT3 mutations impaired multiciliogenesis by blocking commitment to ciliated cell lineages through inhibition of HES6, leading to defective mucociliary transport. Administration of a γ-secretase inhibitor restored HES6 expression and improved ciliogenesis in STAT3 R382W mutant cells. <b>Conclusions:</b> STAT3 dysfunction leads to multicomponent defects in airway epithelial innate defense, which, in conjunction with immune deficiency, contributes to chronic pulmonary infection in STAT3-HIES.

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Journal
American Journal of Respiratory and Critical Care Medicine
Published
2025-06-13
DOI
https://doi.org/10.1164/rccm.202407-1415oc
Citations
2
Primary Topic
Immunodeficiency and Autoimmune Disorders
Type
article
Field-Weighted Citation Impact
1.59
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article

STAT3-Dependent Regulation of CFTR and Ciliogenesis Is Essential for Mucociliary Clearance and Innate Airway Defense in Hyper-IgE Syndrome

Kenichi Okuda, Richard C. Boucher, Charles R. Esther, William J. Kissner et al.
2 citations
American Journal of Respiratory and Critical Care Medicine
Immunodeficiency and Autoimmune Disorders
1.59
article

STAT3-Dependent Regulation of CFTR and Ciliogenesis Is Essential for Mucociliary Clearance and Innate Airway Defense in Hyper-IgE Syndrome

Kenichi Okuda, Richard C. Boucher, Charles R. Esther, William J. Kissner, Deborah M. Cholon, Yu Mikami, Martina Gentzsch, Lynn Zhou, Giorgia Radicioni, Mark I. Gutay, Eszter K. Vladar, Michael Chua, Felicia U. Dizmond, Barbara R. Grubb, Troy D. Rogers, Hong Dang, Patrick R Sears, Scott H. Randell, Matthew R. Markovetz, Brian M. Button, Wanda K. O’Neal, Takanori Asakura, Alexandra F. Freeman, C. Robinson, Nancy L. Quinney, David B. Hill, Camille Ehré, Mehmet Kesımer, Tara N. Guhr Lee, Lawrence E. Ostrowski, Gang Chen, Taraneh Sadritabrizi, Ling Sun, Mei‐Qi Zheng, Koichi Hasegawa, Samantha A. Walls, Kenneth N. Olivier, Anshulika Deshmukh, Xiuya Chang, Daniela Danilova
article en
2 citations

Abstract

<b>Rationale:</b> Hyper-IgE syndrome (STAT3-HIES), also known as Job's syndrome, is a rare immunodeficiency disease typically caused by dominant-negative STAT3 mutations. STAT3-HIES is characterized by chronic pulmonary infection and inflammation, suggesting impaired innate host defense. <b>Objectives:</b> To identify airway epithelial host defense defects caused by STAT3 mutations that, together with immune dysfunction, contribute to recurrent pulmonary infections in STAT3-HIES. <b>Methods:</b> STAT3-HIES sputum was analyzed for biochemical and biophysical properties. STAT3-HIES excised lungs were harvested for histology, and bronchial brush samples were collected for RNA sequencing and <i>in vitro</i> culture. A STAT3-HIES-specific R382W mutation, expressed via lentivirus, and STAT3 knockout (CRISPR/Cas9) were studied in normal human bronchial epithelial cells under basal or inflammatory (IL1β)-stimulated conditions. Effects of STAT3 deficiency on transcriptomics, epithelial ion channel, secretory, antimicrobial, and ciliary functions were assessed. <b>Measurements and Main Results:</b> STAT3-HIES sputum showed increased mucus concentration and viscoelasticity. STAT3-HIES excised lungs exhibited mucus obstruction and elevated IL1β expression. STAT3 mutations reduced CFTR mRNA and protein amounts, impaired CFTR-dependent fluid and mucin secretion, suppressed antimicrobial peptide, cytokine, and chemokine expression, and acidified airway surface liquid at baseline and after IL1β exposure. Notably, mutant STAT3 suppressed IL1R1 expression. Furthermore, STAT3 mutations impaired multiciliogenesis by blocking commitment to ciliated cell lineages through inhibition of HES6, leading to defective mucociliary transport. Administration of a γ-secretase inhibitor restored HES6 expression and improved ciliogenesis in STAT3 R382W mutant cells. <b>Conclusions:</b> STAT3 dysfunction leads to multicomponent defects in airway epithelial innate defense, which, in conjunction with immune deficiency, contributes to chronic pulmonary infection in STAT3-HIES.

American Journal of Respiratory and Critical Care MedicineVol. 211(10)
University of North Carolina at Chapel Hill (US), National Institutes of Health (US), University of North Carolina Health Care (US), Lung Institute (US), Cystic Fibrosis Research Foundation (IT), National Heart, Lung, and Blood Institute (US), National Institute of Allergy and Infectious Diseases (US), University of Colorado Anschutz Medical Campus (US), University of Colorado Denver (US)
Good health and well-being
Openalex Percentile: Top 17%
Immunodeficiency and Autoimmune Disorders
1.59
DOISourceOpenAlex
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