Early growth response 2 as a target of IL-13/STAT6 signaling induces the goblet cell metaplasia of allergic airway epithelia

Abstract

Background: Airway epithelial goblet cell metaplasia is a cardinal feature of allergic asthma and is associated with the morbidity and mortality of this disease, While IL-13/STAT6 signaling is known to drive mucus metaplasia. Early growth response 2 (EGR2), an IL-4/STAT6-responsive transcription factor, is implicated in epithelial remodeling but its specific role in asthmatic goblet cell metaplasia has not been mechanistically established.

Methods: Human asthmatic airway biopsies and murine allergic inflammation models (OVA/challenge) were used to detect the expression of EGR2. Pharmacological STAT6 inhibition (AS1517499), adenoviral EGR2 knockdown, and adeno-associated-viral EGR2 overexpression were employed to dissect hierarchical regulation. Mucin dynamics were quantified via periodic acid-Schiff staining and MUC5AC immunofluorescence staining. Airway hyperresponsiveness (AHR) was assessed by RC system. Chromatin immunoprecipitation (ChIP) and luciferase reporter assays identified direct transcriptional targets.

Results: It was found that expression of EGR2 but not EGR1 and EGR3 was significantly upregulated in airway epithelia of mouse model with allergic airway inflammation or of children with allergic asthma. Whereas inhibition of STAT6 by its specific inhibitor, AS1517499, robustly attenuated not only the EGR2 expression but also the goblet cell metaplasia and mucous hypersecretion in response to IL-13 or allergen. Moreover, adenoviral knockdown of EGR2 expression in airway epithelia significantly attenuated the goblet cell metaplasia and mucous hypersecretion in response to IL-13 or allergen, and consistently attenuated the airway hyperresponsiveness in response to allergen. Whereas adeno-associated-viral overexpression of EGR2 in airway epithelia significantly enhanced the basal as well as allergen-induced goblet cell metaplasia and mucous hypersecretion. Finally, we identify that Muc5ac gene encoding MUC5AC mucin serves as a direct target of EGR2 in response to IL-13.

Conclusions: Together, upregulation of EGR2 expression in allergic airway epithelia contributes to the goblet cell metaplasia and mucous hypersecretion, and intervention of EGR2 is thus a promising approach in the therapy of the cardinal feature of asthma.

Keywords: Early growth response 2; Goblet cell; Muc5ac; Mucous hypersecretion; STAT6.