title: 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.
authors.affiliation: Division of Pulmonary Biology, Cincinnati Children’s Hospital Research Foundation, Cincinnati, Ohio, USA.
authors.forename: Xiaomeng
authors.initials: X
authors.lastname: Ren
authors.forename: Tushar A
authors.initials: TA
authors.lastname: Shah
authors.forename: Vladimir
authors.initials: V
authors.lastname: Ustiyan
authors.forename: Yufang
authors.initials: Y
authors.lastname: Zhang
authors.forename: John
authors.initials: J
authors.lastname: Shinn
authors.forename: Gang
authors.initials: G
authors.lastname: Chen
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Whitsett
authors.forename: Tanya V
authors.initials: TV
authors.lastname: Kalin
authors.forename: Vladimir V
authors.initials: VV
authors.lastname: Kalinichenko
mesh_terms: D000818:Animals; D039741:Antigens, Dermatophagoides / Q000276:immunology; D051940:B7-2 Antigen / Q000235:genetics / Q000378:metabolism; D000073883:CX3C Chemokine Receptor 1; D002454:Cell Differentiation; D002460:Cell Line; D054413:Chemokine CCL11 / Q000235:genetics / Q000378:metabolism; D054423:Chemokine CCL24 / Q000235:genetics / Q000378:metabolism; D002908:Chronic Disease; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D004848:Epithelium / Q000378:metabolism; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D017353:Gene Deletion; D005786:Gene Expression Regulation; D020397:Goblet Cells / Q000166:cytology / Q000276:immunology / Q000473:pathology*; D007249:Inflammation / Q000276:immunology / Q000473:pathology*; D008168:Lung / Q000276:immunology / Q000503:physiopathology; D008679:Metaplasia / Q000276:immunology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011014:Pneumonia / Q000276:immunology / Q000473:pathology; D054390:Receptors, CCR2 / Q000235:genetics / Q000378:metabolism; D019707:Receptors, Chemokine / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D039741:Antigens, Dermatophagoides; D051940:B7-2 Antigen; D000073883:CX3C Chemokine Receptor 1; C515457:Ccl11 protein, mouse; C515485:Ccl24 protein, mouse; C515335:Ccr2 protein, mouse; C497965:Cd86 protein, mouse; D054413:Chemokine CCL11; D054423:Chemokine CCL24; C471885:Cx3cr1 protein, mouse; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; C491524:Foxm1 protein, mouse; D054390:Receptors, CCR2; D019707:Receptors, Chemokine; D014157:Transcription Factors