Abstract
Since long-term corticosteroid treatment is associated with emerging opportunistic fungal infections causing high morbidity and mortality in immune-suppressed individuals, here we characterized the impact of dexamethasone (Dex) treatment on Aspergillus fumigatus-related immune modulation. We found by high content screening and flow cytometric analyses that during monocyte-to-macrophage differentiation, as little as 0.1 µg/mL Dex resulted in a shift in macrophage polarization from M1 to M2-like macrophages. This macrophage repolarization mediated via Dex was characterized by significant upregulation of the M2 marker CD163 and downmodulation of M1 markers CD40 and CD86 as well as changes in phenotypic properties and adherence. These Dex-mediated phenotypic alterations were furthermore associated with a metabolic switch in macrophages orchestrated via PKM2. Such treated macrophages lost their ability to prevent Aspergillus fumigatus germination, which was correlated with accelerated fungal growth, destruction of macrophages, and induction of an anti-inflammatory cytokine profile. Taken together, repolarization of macrophages following corticosteroid treatment and concomitant switch to an anti-inflammatory phenotype might play a prominent role in triggering invasive aspergillosis (IA) due to suppression of innate immunological responses necessary to combat extensive fungal outgrowth.
Highlights
Macrophages are the predominant phagocytic cells in the pulmonary system arising from bone-marrow-derived monocyte precursors [1,2]
To see if the metabolic activity of macrophages is altered upon Dex treatment during differentiation, we studied the expression levels of the enzyme Pyruvate kinase isoform M2 (PKM2) in GM, Dex- and M-MDMs, which plays a rate-limiting role in metabolic activities in terms of facilitating glycolysis
Glucocorticosteroids like Dexamethasone or Prednisolone have been suggested to play a role in aggravating fungal infection [16]
Summary
Macrophages are the predominant phagocytic cells in the pulmonary system arising from bone-marrow-derived monocyte precursors [1,2]. They are recruited to sites of infection, making them crucial first-line defenders within the innate immune system against bacterial and fungal pathogens that are able to breach the epithelial barrier [3,4,5]. Macrophages exhibit flexibility in their functional and phenotypic capacities, which are dictated by specific environmental stimuli [6] They exist as a heterogeneous population with a high degree of metabolic diversity [7,8]. Aspergillus (A.) fumigatus is the most prevalent saprophytic fungal pathogen in immunocompromised individuals [12,13,14], and it invades both the upper and lower respiratory tracts, resulting in severe pulmonary diseases, such as IA [13,15,16,17]
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