Author:
Sun Ling,Walls Samantha A.,Dang Hong,Quinney Nancy L.,Sears Patrick R.,Sadritabrizi Taraneh,Hasegawa Koichi,Okuda Kenichi,Asakura Takanori,Chang Xiuya,Zheng Meiqi,Mikami Yu,Dizmond Felicia U.,Danilova Daniela,Zhou Lynn,Deshmukh Anshulika,Cholon Deborah M.,Radicioni Giorgia,Rogers Troy D.,Kissner William J.,Markovetz Matthew R.,Guhr Lee Tara N.,Gutay Mark I.,Esther Charles R.,Chua Michael,Grubb Barbara R.,Ehre Camille,Kesimer Mehmet,Hill David B.,Ostrowski Lawrence E.,Button Brian,Gentzsch Martina,Robinson Chevalia,Olivier Kenneth N.,Freeman Alexandra F.,Randell Scott H.,O’Neal Wanda K.,Boucher Richard C.,Chen Gang
Abstract
AbstractRationaleHyper IgE syndrome (STAT3-HIES), also known as Job’s syndrome, is a rare immunodeficiency disease typically caused by dominant-negative STAT3 mutations. STAT3-HIES syndrome is characterized by chronic pulmonary infection and inflammation, suggesting impairment of pulmonary innate host defense.ObjectivesTo identify airway epithelial host defense defects consequent to STAT3 mutations that, in addition to reported mutant STAT3 immunologic abnormalities, produce pulmonary infection.MethodsSTAT3-HIES sputum was evaluated for biochemical/biophysical properties. STAT3-HIES excised lungs were harvested for histology; bronchial brush samples were collected for RNA sequencing and in vitro culture. A STAT3-HIES-specific mutation (R382W), expressed by lentiviruses, and a STAT3 knockout, generated by CRISPR/Cas9, were maintained in normal human bronchial epithelia under basal or inflammatory (IL1β) conditions. Effects of STAT3 deficiency on transcriptomics, and epithelial ion channel, secretory, antimicrobial, and ciliary functions were assessed.Measurements and Main ResultsMucus concentrations and viscoelasticity were increased in STAT3-HIES sputum. STAT3-HIES excised lungs exhibited mucus obstruction and elevated IL1β expression. STAT3 deficiency impaired CFTR-dependent fluid and mucin secretion, inhibited expression of antimicrobial peptides, cytokines, and chemokines, and acidified airway surface liquid at baseline and post-IL1β exposure in vitro. Notably, mutant STAT3 suppressed IL1R1 expression. STAT3 mutations also inhibited ciliogenesis in vivo and impaired mucociliary transport in vitro, a process mediated via HES6 suppression. Administration of a γ-secretase inhibitor increased HES6 expression and improved ciliogenesis in STAT3 R382W mutant cells.ConclusionsSTAT3 dysfunction leads to multi-component defects in airway epithelial innate defense, which, in conjunction with STAT3-HIES immune deficiency, contributes to chronic pulmonary infection.
Publisher
Cold Spring Harbor Laboratory