Exposure to mold proteases stimulates mucin production in airway epithelial cells through Ras/Raf1/ERK signal pathway.

Xianxian Wu,Boram Lee,Lingxiang Zhu,Yin Chen,Zhi Ding,Hong Wei Chu

doi:10.1371/journal.pone.0231990

Abstract

Environmental mold (fungus) exposure poses a significant threat to public health by causing illnesses ranging from invasive fungal diseases in immune compromised individuals to allergic hypertensive diseases such as asthma and asthma exacerbation in otherwise healthy people. However, the molecular pathogenesis has not been completely understood, and treatment options are limited. Due to its thermo-tolerance to the normal human body temperature, Aspergillus. fumigatus (A.fumigatus) is one of the most important human pathogens to cause different lung fungal diseases including fungal asthma. Airway obstruction and hyperresponsiveness caused by mucus overproduction are the hallmarks of many A.fumigatus induced lung diseases. To understand the underlying molecular mechanism, we have utilized a well-established A.fumigatus extracts (AFE) model to elucidate downstream signal pathways that mediate A.fumigatus induced mucin production in airway epithelial cells. AFE was found to stimulate time- and dose-dependent increase of major airway mucin gene expression (MUC5AC and MUC5B) partly via the elevation of their promoter activities. We also demonstrated that EGFR was required but not sufficient for AFE-induced mucin expression, filling the paradoxical gap from a previous study using the same model. Furthermore, we showed that fungal proteases in AFE were responsible for mucin induction by activating a Ras/Raf1/ERK signaling pathway. Ca2+ signaling, but ROS, both of which were stimulated by fungal proteases, was an indispensable determinant for ERK activation and mucin induction. The discovery of this novel pathway likely contributes to our understanding of the pathogenesis of fungal sensitization in allergic diseases such as fungal asthma.

Highlights

Aspergillus is a group of molds with around 200 species commonly found both indoor and outdoor [1, 2]
MUC5AC and MUC5B transcripts were measured in epithelial cells reacted with three different concentrations of A. fumigatus extracts (AFE) for 6 and 24 hrs, respectively
In the case of Aspergillus, diseases caused by opportunistic infection such as aspergilloma and invasive pulmonary aspergillosis are devastating and sometimes lethal, they rarely occur in healthy individuals [1, 50, 51]

Summary

Introduction

Aspergillus is a group of molds with around 200 species commonly found both indoor and outdoor [1, 2]. A.fumigatus can cause other severe fungal diseases such as aspergilloma, allergic bronchopulmonary aspergillosis (ABPA) and invasive aspergillosis [1, 14, 15] in individuals with a compromised immune system (e.g. AIDS, patients receiving transplant, or under immune-suppressive medications) [15]. In these individuals, A.fumigatus could spread from the initial site of infection in the lung to other organs and lead to fatal results [15, 16]. Mucus overproduction is associated with almost all of A.fumigatus induced airway diseases including ABPA and fungal asthma. AFE increased Ras/Raf1/ERK pathway that was likely responsible for mucin induction in the epithelial cells

Materials and methods

Results

Discussion