Foxa2 Regulates Leukotrienes to Inhibit Th2-mediated Pulmonary Inflammation

Abstract

Foxa2 is a member of the Forkhead family of nuclear transcription factors that is highly expressed in respiratory epithelial cells of the developing and mature lung. Foxa2 is required for normal airway epithelial differentiation, and its deletion causes goblet-cell metaplasia and Th2-mediated pulmonary inflammation during postnatal development. Foxa2 expression is inhibited during aeroallergen sensitization and after stimulation with Th2 cytokines, when its loss is associated with goblet-cell metaplasia. Mechanisms by which Foxa2 controls airway epithelial differentiation and Th2 immunity are incompletely known. During the first 2 weeks after birth, the loss of Foxa2 increases the production of leukotrienes (LTs) and Th2 cytokines in the lungs of Foxa2 gene-targeted mice. Foxa2 expression inhibited 15-lipoxygenase (Alox15) and increased Alox5 transcription, each encoding key lipoxygenases associated with asthma. The inhibition of the cysteinyl LT (CysLT) signaling pathway by montelukast inhibited IL-4, IL-5, eotaxin-2, and regulated upon activation normal T cell expressed and presumably secreted expression in the developing lungs of Foxa2 gene-targeted mice. Montelukast inhibited the expression of genes regulating mucus metaplasia, including Spdef, Muc5ac, Foxa3, and Arg2. Foxa2 plays a cell-autonomous role in the respiratory epithelium, and is required for the suppression of Th2 immunity and mucus metaplasia in the developing lung in a process determined in part by its regulation of the CysLT pathway.

Gene Expression Correlated with Severe Asthma Characteristics Reveals Heterogeneous Mechanisms of Severe Disease

“…Finally, 19 (58%) subjects had moderate levels (25-75th percentile), and were designated as T1 high/T2 mod. T1 high/T2 low were the youngest (median, 24 yr; interquartile range [IQR], [19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35], and statistically younger than T2 mod. They had the lowest FE NO (median, 16 ppb; IQR, 11-20), were statistically lower than T1 high/T2 high, had the lowest incidence of CRS, highest AQLQ (median, 5; IQR, 4-5.5), highest FEV 1 % predicted (median, 78%; IQR, 71-100), and the lowest rate of ED/hosp.…”

Innate Immunity to Respiratory Infection in Early Life

“…In the developing lung, it regulates epithelial differentiation and controls goblet cell hyperplasia. It also has immunoregulatory functions and limits type-2 immunity through inhibition of the cysteinyl LT signaling pathway (83,141,144).…”

DNA Methylation: A Potential Biomarker of Chronic Obstructive Pulmonary Disease

“…SAM-pointed domain, a transcription factors containing ETS like factor (SPDEF) and forkhead box protein A2 (FOXA2), regulates the differentiation of goblet cells. Airway mucin 5AC, secreted by SPDEF, is aggravated the differentiation of goblet cells and mucin production ( Park et al, 2007 ; Chen et al, 2009 ; Rajavelu et al, 2015 ), while FOXA2 effectively inhibited the differentiation of pulmonary goblet cells ( Tang et al, 2013 ). Song et al (2017) had found hypermethylation of CPG-8 in the promoter of SPDEF and hypomethylation of CpG-14 and CpG-15 in FOXA2 , was identified the abnormal methylation of SPDEF and FOXA2 during the differentiation of goblet cells is the basic factor of mucus hypersecretion in COPD, thus providing a new approach to understand mucus hypersecretion from the perspective of epigenetics.…”