Ling Sun, Samantha A Walls, Hong Dang, Nancy L Quinney, Patrick R Sears, Taraneh Sadritabrizi, Koichi Hasegawa, Kenichi Okuda, Takanori Asakura, Xiuya Chang, Meiqi Zheng, Yu Mikami, Felicia U Dizmond, Daniela Danilova, Lynn Zhou, Anshulika Deshmukh, Deborah M Cholon, Giorgia Radicioni, Troy D Rogers, William J Kissner, Matthew R Markovetz, Tara N Guhr Lee, Mark I Gutay, Charles R Esther, Michael Chua, Barbara R Grubb, Camille Ehre, Mehmet Kesimer, David B Hill, Lawrence E Ostrowski, Brian Button, Martina Gentzsch, Chevalia Robinson, Kenneth N Olivier, Alexandra F Freeman, Scott H Randell, Eszter Vladar, Wanda K O'Neal, Richard C Boucher, Gang Chen
{"title":"stat3依赖性调节CFTR和纤毛发生对高ige综合征的纤毛粘液清除和先天气道防御至关重要。","authors":"Ling Sun, Samantha A Walls, Hong Dang, Nancy L Quinney, Patrick R Sears, Taraneh Sadritabrizi, Koichi Hasegawa, Kenichi Okuda, Takanori Asakura, Xiuya Chang, Meiqi Zheng, Yu Mikami, Felicia U Dizmond, Daniela Danilova, Lynn Zhou, Anshulika Deshmukh, Deborah M Cholon, Giorgia Radicioni, Troy D Rogers, William J Kissner, Matthew R Markovetz, Tara N Guhr Lee, Mark I Gutay, Charles R Esther, Michael Chua, Barbara R Grubb, Camille Ehre, Mehmet Kesimer, David B Hill, Lawrence E Ostrowski, Brian Button, Martina Gentzsch, Chevalia Robinson, Kenneth N Olivier, Alexandra F Freeman, Scott H Randell, Eszter Vladar, Wanda K O'Neal, Richard C Boucher, Gang Chen","doi":"","DOIUrl":null,"url":null,"abstract":"<p><strong>Rationale: </strong>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.</p><p><strong>Objectives: </strong>To identify airway epithelial host defense defects caused by STAT3 mutations that, together with immune dysfunction, contribute to recurrent pulmonary infections in STAT3-HIES.</p><p><strong>Methods: </strong>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 in vitro 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.</p><p><strong>Measurements and main results: </strong>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 levels, impaired CFTR-dependent fluid and mucin secretion, suppressed antimicrobial peptide, cytokine, and chemokine expression, and acidified airway surface liquid at baseline and post-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, improved ciliogenesis in STAT3 R382W mutant cells.</p><p><strong>Conclusions: </strong>STAT3 dysfunction leads to multi-component defects in airway epithelial innate defense, which, in conjunction with immune deficiency, contributes to chronic pulmonary infection in STAT3-HIES.</p>","PeriodicalId":7664,"journal":{"name":"American journal of respiratory and critical care medicine","volume":" ","pages":"None"},"PeriodicalIF":19.3000,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"STAT3-dependent Regulation of CFTR and Ciliogenesis Is Essential for Mucociliary Clearance and Innate Airway Defense in Hyper-IgE Syndrome.\",\"authors\":\"Ling Sun, Samantha A Walls, Hong Dang, Nancy L Quinney, Patrick R Sears, Taraneh Sadritabrizi, Koichi Hasegawa, Kenichi Okuda, Takanori Asakura, Xiuya Chang, Meiqi Zheng, Yu Mikami, Felicia U Dizmond, Daniela Danilova, Lynn Zhou, Anshulika Deshmukh, Deborah M Cholon, Giorgia Radicioni, Troy D Rogers, William J Kissner, Matthew R Markovetz, Tara N Guhr Lee, Mark I Gutay, Charles R Esther, Michael Chua, Barbara R Grubb, Camille Ehre, Mehmet Kesimer, David B Hill, Lawrence E Ostrowski, Brian Button, Martina Gentzsch, Chevalia Robinson, Kenneth N Olivier, Alexandra F Freeman, Scott H Randell, Eszter Vladar, Wanda K O'Neal, Richard C Boucher, Gang Chen\",\"doi\":\"\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Rationale: </strong>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.</p><p><strong>Objectives: </strong>To identify airway epithelial host defense defects caused by STAT3 mutations that, together with immune dysfunction, contribute to recurrent pulmonary infections in STAT3-HIES.</p><p><strong>Methods: </strong>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 in vitro 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.</p><p><strong>Measurements and main results: </strong>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 levels, impaired CFTR-dependent fluid and mucin secretion, suppressed antimicrobial peptide, cytokine, and chemokine expression, and acidified airway surface liquid at baseline and post-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, improved ciliogenesis in STAT3 R382W mutant cells.</p><p><strong>Conclusions: </strong>STAT3 dysfunction leads to multi-component defects in airway epithelial innate defense, which, in conjunction with immune deficiency, contributes to chronic pulmonary infection in STAT3-HIES.</p>\",\"PeriodicalId\":7664,\"journal\":{\"name\":\"American journal of respiratory and critical care medicine\",\"volume\":\" \",\"pages\":\"None\"},\"PeriodicalIF\":19.3000,\"publicationDate\":\"2025-05-02\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"American journal of respiratory and critical care medicine\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CRITICAL CARE MEDICINE\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"American journal of respiratory and critical care medicine","FirstCategoryId":"3","ListUrlMain":"","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CRITICAL CARE MEDICINE","Score":null,"Total":0}
STAT3-dependent Regulation of CFTR and Ciliogenesis Is Essential for Mucociliary Clearance and Innate Airway Defense in Hyper-IgE Syndrome.
Rationale: 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.
Objectives: To identify airway epithelial host defense defects caused by STAT3 mutations that, together with immune dysfunction, contribute to recurrent pulmonary infections in STAT3-HIES.
Methods: 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 in vitro 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.
Measurements and main results: 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 levels, impaired CFTR-dependent fluid and mucin secretion, suppressed antimicrobial peptide, cytokine, and chemokine expression, and acidified airway surface liquid at baseline and post-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, improved ciliogenesis in STAT3 R382W mutant cells.
Conclusions: STAT3 dysfunction leads to multi-component defects in airway epithelial innate defense, which, in conjunction with immune deficiency, contributes to chronic pulmonary infection in STAT3-HIES.
期刊介绍：
The American Journal of Respiratory and Critical Care Medicine focuses on human biology and disease, as well as animal studies that contribute to the understanding of pathophysiology and treatment of diseases that affect the respiratory system and critically ill patients. Papers that are solely or predominantly based in cell and molecular biology are published in the companion journal, the American Journal of Respiratory Cell and Molecular Biology. The Journal also seeks to publish clinical trials and outstanding review articles on areas of interest in several forms. The State-of-the-Art review is a treatise usually covering a broad field that brings bench research to the bedside. Shorter reviews are published as Critical Care Perspectives or Pulmonary Perspectives. These are generally focused on a more limited area and advance a concerted opinion about care for a specific process. Concise Clinical Reviews provide an evidence-based synthesis of the literature pertaining to topics of fundamental importance to the practice of pulmonary, critical care, and sleep medicine. Images providing advances or unusual contributions to the field are published as Images in Pulmonary, Critical Care, Sleep Medicine and the Sciences.
A recent trend and future direction of the Journal has been to include debates of a topical nature on issues of importance in pulmonary and critical care medicine and to the membership of the American Thoracic Society. Other recent changes have included encompassing works from the field of critical care medicine and the extension of the editorial governing of journal policy to colleagues outside of the United States of America. The focus and direction of the Journal is to establish an international forum for state-of-the-art respiratory and critical care medicine.
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