The Club Cell Marker SCGB1A1 Downstream of FOXA2 is Reduced in Asthma

Abstract

Human SCGB1A1 protein has been shown to be significantly reduced in BAL, sputum, and serum from humans with asthma as compared with healthy individuals. However, the mechanism of this reduction and its functional impact have not been entirely elucidated. By mining online datasets, we found that the mRNA of SCGB1A1 was significantly repressed in brushed human airway epithelial cells from individuals with asthma, and this repression appeared to be associated with reduced expression of FOXA2. Consistently, both Scgb1A1 and FoxA2 were downregulated in an ovalbumin-induced mouse model of asthma. Furthermore, compared with wild-type mice, Scgb1a1 knockout mice had increased airway hyperreactivity and inflammation when they were exposed to ovalbumin, confirming the antiinflammatory role of Scgb1a1 in protection against asthma phenotypes. To search for potential asthma-related stimuli of SCGB1A1 repression, we tested T-helper cell type 2 cytokines. Both IL-4 and IL-13 repressed epithelial expression of SCGB1A1 and FOXA2. Importantly, infection of epithelial cells with human rhinovirus similarly reduced expression of these two genes, which suggests that FOXA2 may be the common regulator of SCGB1A1. To establish the causal role of reduced FOXA2 in SCGB1A1 repression, we demonstrated that FOXA2 was required for SCGB1A1 expression at baseline. FOXA2 overexpression was sufficient to drive promoter activity and expression of SCGB1A1 and was also able to restore the repressed SCGB1A1 expression in IL-13-treated or rhinovirus-infected cells. Taken together, these findings suggest that low levels of epithelial SCGB1A1 in asthma are caused by reduced FOXA2 expression.

Epithelial barriers in allergy and asthma

“…These cells are dome-shaped cubical nonciliated cells that secrete a specific protein belonging to the secretoglobin family (SCGB1A1). 29…”

“…30 Reduced club cell numbers and SCGB1A1 are reported in patients with COPD, and in patients with asthma and was associated with disease severity. 29,31 Recently, with the use of single-cell RNA sequencing, Montoro et al 20 described a novel subset of club cells in murine airways. Hillock club cells express squamous epithelial markers Krt4 and Krt13, are only found in epithelial regions with high turnover, and have characteristic barrier function (claudin 3) and immunomodulatory (galectin 3 and annexin A1) properties.…”

An Elusive Fox that Suppresses Scgb1a1 in Asthma Has Been Found

“…In this issue of the Journal , Zhu and colleagues (pp. 695–704), report on what may be a key observation in furthering our understanding of why the airway epithelium of individuals with asthma or COPD have less secretoglobin family 1A member 1 (SCGB1A1; also known as club cell secretory protein [CCSP], CC10, and CC16) compared with healthy control subjects (2). In their studies, they discovered that viral infections and Th2 cytokines inhibit expression of SCGB1A1 by inhibiting expression of the transcription factor forkhead box A2 (FOXA2), which is known to regulate Th2-mediated inflammation and goblet cell hyperplasia.…”

“…Cartoon model summarizing the key findings of Zhu and colleagues (2). The production of T-helper cell type 2 cytokines such as IL-4 and IL-13 or infection with rhinovirus suppresses expression of FOXA2 in club cells.…”

Clara Cell 10-kDa Protein is a Sensitive Biomarker to Identify Th2 Subtype Inflammatory Phenotypes of Asthma

“…Other studies found that CC10 expression in lung tissue was regulated by in ammatory cytokines. IL-4 and IL-13 inhibited CC10 production [24] , whereas interferon (INF) -γ and IL-10 could promote CC10 production [25,26] . The counter effect of Th1 and Th2 cytokines on CC10 production may ensure the stability of discrepant expression in different asthma phenotypes.…”