Airway epithelial SPDEF integrates goblet cell differentiation and pulmonary Th2 inflammation

摘要

Epithelial cells that line the conducting airways provide the initial barrier and innate immune responses to the abundant particles, microbes, and allergens that are inhaled throughout life. The transcription factors SPDEF and FOXA3 are both selectively expressed in epithelial cells lining the conducting airways, where they regulate goblet cell differentiation and mucus production. Moreover, these transcription factors are upregulated in chronic lung disorders, including asthma. Here, we show that expression of SPDEF or FOXA3 in airway epithelial cells in neonatal mice caused goblet cell differentiation, spontaneous eosinophilic inflammation, and airway hyperresponsiveness to methacholine. SPDEF expression promoted DC recruitment and activation in association with induction of Il33 , Csf2 , thymic stromal lymphopoietin ( Tslp ), and Ccl20 transcripts. Increased Il4 , Il13 , Ccl17 , and Il25 expression was accompanied by recruitment of Th2 lymphocytes, group 2 innate lymphoid cells, and eosinophils to the lung. SPDEF was required for goblet cell differentiation and pulmonary Th2 inflammation in response to house dust mite (HDM) extract, as both were decreased in neonatal and adult Spdef~(–/–) mice compared with control animals. Together, our results indicate that SPDEF causes goblet cell differentiation and Th2 inflammation during postnatal development and is required for goblet cell metaplasia and normal Th2 inflammatory responses to HDM aeroallergen. Keywords: Development, Genetics, Immunology, Inflammation, TherapeuticsIntroductionThe tracheobronchial tree is lined by a diversity of epithelial cells including basal, ciliated, serous, and goblet cells that make unique contributions to mucociliary clearance, innate immunity, and recruitment and activation of professional immune cells that mediate inflammatory responses to environmental exposures (1–5). The nature and extent of innate and acquired immune responses to respiratory pathogens and allergens are influenced genetically and developmentally and by exposure to specific pathogens and toxicants. There is increasing evidence that pulmonary immune responses are initiated early in development, in utero, and during infancy (6–10). Mechanisms by which early exposures of the lung to pathogens instruct the acquisition of innate and acquired immunity are of considerable interest. For example, wheezing following infection of infants to rhinovirus (RV) strongly predicts subsequent risks for development of asthma later in life (11, 12). The observations that the incidence of childhood asthma is lower in infants exposed to an abundance of bacterial and fungal microbes supports the concept that early environmental exposures influence the development of asthma (13). Mechanisms influencing the acquisition of Th1- and Th2-mediated immunity in infancy have important implications for host defense and allergic responses that mediate subsequent responses to environmental stimuli throughout life (14). Recent studies in gnotobiotic mice demonstrate an age-dependent programming of invariant NK cells that influences subsequent allergic responses in the lung (14). Respiratory epithelial cells are increasingly recognized as important modulators of innate immune responses that govern inflammatory and immune responses to pathogens and toxicants via their synthesis of chemokines and cytokines, growth factors that regulate the migration and activation of the diverse immune cells to sites of injury (refs. 15–17, for review). Airway epithelial cells mount rapid and robust responses to a diversity of pathogen-associated molecular pattern molecules (PAMPs), damage-associated molecular pattern molecules (DAMPs) that influence both innate immune and repair processes that maintain pulmonary homeostasis. The airway epithelial barrier is maintained by a diversity of specific epithelial cell types that each contribute uniquely in response to airway injury. Basal and nonciliated progenitor cells serve as precursors from which ciliated and goblet cells are derived (2, 18). Airway goblet cells synthesize and secrete a variety of mucins and other proteins that play important roles in mucociliary clearance and host defense (19). While the activation of goblet cells and mucus secretion are normal responses to acute injury and infection, chronic goblet cell hyperplasia and metaplasia are features of common chronic pulmonary diseases, including asthma, cystic fibrosis (CF), and chronic obstructive pulmonary disease (COPD), wherein mucus hyperproduction contributes to the mortality and morbidity associated with these disorders (19–21).Airway goblet cell differentiation is influenced by the transcription factors SAM-pointed domain–containing ETS-like factor (SPDEF) and forkhead ortholog A3 (FOXA3), which are selectively expressed in airway goblet cells and induced by toxicants, aeroallergens, viral infections, and cytokines. SPDEF is sufficient and required for goblet cell differentiation and mucus pr