Abstract
Lung immunity and susceptibility to infections is subject to interactions between the epithelial layer and immune cells residing in the pulmonary space. Aspergillus (A.) fumigatus, the most prevalent pathogenic fungus, affects both upper and lower respiratory tracts of immunocompromised hosts. Several reports implicate corticosteroids as a major risk factor due to their anti-inflammatory and immunosuppressive effects, which are exacerbated by long-term treatment regimens. Here we demonstrate for the first time the influence of dexamethasone when it comes to germination and hyphae formation of A. fumigatus in the presence of macrophages within a highly differentiated air–liquid interphase (ALI) epithelial/immune lung model. We illustrate suppressed mucus production within the highly differentiated 3D respiratory model as well as significantly decreased cilia beat frequencies by dexamethasone treatment. This goes along with corticosteroid-mediated macrophage M2 polarization within the epithelial/immune microenvironment. Therefore, we here showed that corticosteroids promote enhanced fungal growth and invasion A. fumigatus by creating a suppressive environment affecting both epithelial as well as immune cells.
Highlights
During the differentiation period of 21 days in air–liquid interphase (ALI), TEER values within the 3D respiratory model were analyzed to confirm the integrity of tight junctions (Figure 1a)
To characterize whether dexamethasone has an effect on mucus production, we evaluated the abundance of mucins MUC5AC and MUC1 in primary differentiated epithelia
Comparison to untreated controls, hyphae overgrowth, referred to as trans-epithelial we examined the impact of dexamethasone on macrophage migration towards a reinvasion, was clearly visible in dexamethasone-treated conditions confirming that the combinant human GM-CSF (50 ng/mL) gradient
Summary
The generation of more human-like in vitro models incorporating complex parameters, such as primary cells and extensive vasculature, is imperative during preliminary drug screening studies so as to avoid situations where animal experimental outcomes do not translate reliably, such as in the TGN1412 trial disaster of 2006 [3]. Ciliated cells actively eliminate debris and unwanted particles from the pulmonary system in conjunction with club as well as goblet cells which secret mucus, surfactants, and antimicrobial fluids leading to direct impediment of microbial development [7]. These cells collectively participate in the first-line defense against pulmonary invasion of pathogens in association with immune cells, such as macrophages [8]. Since the epithelial lining covers the majority of the human airway [10], it generally determines the outcome of respiratory diseases
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