FOXM1 Promotes Allergen-Induced Goblet Cell Metaplasia and Pulmonary Inflammation

Abstract

Chronic airway disorders, including chronic obstructive pulmonary disease (COPD), cystic fibrosis, and asthma, are associated with persistent pulmonary inflammation and goblet cell metaplasia and contribute to significant morbidity and mortality worldwide. While the molecular pathogenesis of these disorders is actively studied, little is known regarding the transcriptional control of goblet cell differentiation and mucus hyperproduction. Herein, we demonstrated that pulmonary allergen sensitization induces expression of FOXM1 transcription factor in airway epithelial and inflammatory cells. Conditional deletion of the Foxm1 gene from either airway epithelium or myeloid inflammatory cells decreased goblet cell metaplasia, reduced lung inflammation, and decreased airway resistance in response to house dust mite allergen (HDM). FOXM1 induced goblet cell metaplasia and Muc5AC expression through the transcriptional activation of Spdef. FOXM1 deletion reduced expression of CCL11, CCL24, and the chemokine receptors CCR2 and CX3CR1, resulting in decreased recruitment of eosinophils and macrophages to the lung. Deletion of FOXM1 from dendritic cells impaired the uptake of HDM antigens and decreased cell surface expression of major histocompatibility complex II (MHC II) and costimulatory molecule CD86, decreasing production of Th2 cytokines by activated T cells. Finally, pharmacological inhibition of FOXM1 by ARF peptide prevented HDM-mediated pulmonary responses. FOXM1 regulates genes critical for allergen-induced lung inflammation and goblet cell metaplasia.

Airway Goblet Cells Secrete Pro-Inflammatory Cytokines, Chemokines, and Growth Factors

“…Forkhead box protein M1 transforms airway epithelial cells into a goblet cell phenotype and promotes lung inflammation. 18 Lipopolysaccharide stimulates both mucin and cytokine CXCL8 secretion in HT29 goblet cells. 19 Pseudomonal airway infection increases mucin secretion through the release of inflammatory cytokines and growth factors.…”

Three cheers for the goblet cell: maintaining homeostasis in mucosal epithelia

“…Mouse models of allergen-induced goblet cell metaplasia have been essential to our understanding of the mechanisms regulating goblet cell differentiation in the lung, and have uncovered a complex network by which inflammatory stimuli govern goblet cell associated genes [22,44,81,82,108]. Furthermore, expression changes in Notch signaling [109,110], Foxa2 [78], Foxa3 [81,82], Agr2 [82], and SPDEF [81,82] have been reported in bronchial samples from patients suffering from chronic obstructive pulmonary disease, asthma, or cystic fibrosis (Table 1).…”

FOXF1 Transcription Factor Is Required for Formation of Embryonic Vasculature by Regulating VEGF Signaling in Endothelial Cells

“…Paraffin sections were stained with hematoxylin and eosin (H&E) or used for immunohistochemical staining as described 26, 27 . Primary antibodies and detection systems are listed in Supplemental Material.…”