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

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. Ca 2+ 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.

Proteases, Mucus, and Mucosal Immunity in Chronic Lung Disease

“…Notably, proteases released by Aspergillus fumigatus , a fungus that is highly prevalent in the early CF lung, induce MUC5AC expression [ 66 , 67 ]. A more recent study identified a Ras/Raf1/extracellular signal-regulated kinase (ERK) signalling pathway through which mucin expression was induced by fungal proteases [ 68 ]. Upregulation of MUC5AC by NE and other proteases in CLD will alter the MUC5AC/MUC5B ratio in favour of MUC5AC.…”

Lysophosphatidylserine Induces MUC5AC Production via the Feedforward Regulation of the TACE-EGFR-ERK Pathway in Airway Epithelial Cells in a Receptor-Independent Manner

“…Moreover, neither DPI nor NAC inhibited LysoPS-induced MUC5AC production, suggesting that ROS is unlikely to be involved in LysoPS-induced TACE activation. ROS-independent mucin production has also been reported in mold protease-exposed airway epithelial cells [ 47 ].…”

Analysis of miRNA Profiles and the Regulatory Network in Congenital Pulmonary Airway Malformations

“…Of these, Ras, MAPK, and PI3K-Akt signaling pathways have been elucidated in different lung diseases. For example, ERK phosphorylation as a marker of Ras activity has shown prognostic value in non-small cell lung cancer ( 40 ), and exposure to mold proteases stimulated mucin production in airway epithelial cells through Ras/Raf1/ERK signal pathway ( 41 ). Furthermore, Apelin-36 protects against lipopolysaccharide-induced acute lung injury by inhibiting the ASK1/MAPK signaling pathway ( 42 ), whereas fibro growth factor-2 protects against acute lung injury by activating the PI3K/Akt signaling pathway ( 43 ).…”