Dexamethasone Creates a Suppressive Microenvironment and Promotes Aspergillus fumigatus Invasion in a Human 3D Epithelial/Immune Respiratory Model

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.

Enhanced tendon healing by a tough hydrogel with an adhesive side and high drug-loading capacity

“…Following JTA and JTA+CORT treatment, cellularity and M2 macrophage polarization was increased, the latter suggested by the increase in Arg1 immuno-positive CD68 expressing cells. The mechanism of M2 macrophage polarization remains however ambiguous, because chitosan present in the adhesive layer of the JTA has been shown to induced M2 polarization 63 – 67 , similar to triamcinolone acetonide alone 68 , 69 . In the present study, the pharmacodynamic activity of triamcinolone acetonide following release from the JTA was demonstrated by the feedback-inhibition of endogenous corticosterone levels at day 2 post-implantation, which occurred in concert with a decrease in serum GROα levels, a chemokine affecting recruitment and activation of neutrophils.…”

The breathtaking world of human respiratory in vitro models: Investigating lung diseases and infections in 3D models, organoids, and lung‐on‐chip

“…3D models of the respiratory tract and lung are highly suited to assess the first interactions of Aspergillus species with the human host and co-cultures with immune cells like DCs and macrophages revealed full functionality upon infection with the fungus [33,34,61]. In co-culture studies with macrophages, Luvanda et al [34] illustrated that corticosteroids like dexamethasone create an immunosuppressive microenvironment, thus promoting enhanced A. fumigatus growth and invasion. Moreover, the authors illustrated that this went along with corticosteroid-induced macrophage M2 polarization within the immune-competent tissue environment.…”

“…Immune cells are typically added on the basolateral side and therefore interact with the epithelial cells via direct cell-cell contact or cytokine release. The addition of immune cells, such as DCs, macrophages, neutrophils, T, or B cells, mimic the complex cellular network within the lung in a more realistic way and examples of co-cultures are neutrophils with HAE cells [37], macrophages with HAE [38] or SAE cells [33], or dendritic cells with HAE cells [34]. These co-culture models are especially of interest to study infection at entry sites as illustrated in Fig.…”

Guidelines for visualization and analysis of DC in tissues using multiparameter fluorescence microscopy imaging methods

“…Most importantly, we can perform live or fixed cell imaging approaches, for instance 3D visualization of host-pathogen interactions, which are vital to characterize cellular processes, such as cell migration and differentiation. This highly differentiated lung and/or APC model has already been successfully used to study the cross-talk between viruses and cells of the airway in A. fumigatus [83,84] and SARS-CoV-2 [73,75] infected respiratory tissue.…”