Luvanda Maureen K, Posch Wilfried, Vosper Jonathan, Zaderer Viktoria, Noureen Asma, Lass-Flörl Cornelia, Wilflingseder Doris
Institute of Hygiene and Medical Microbiology, Medical University of Innsbruck, 6020 Innsbruck, Austria.
Institute of Medical Biochemistry, Medical University of Innsbruck, 6020 Innsbruck, Austria.
J Fungi (Basel). 2021 Jan 20;7(2):70. doi: 10.3390/jof7020070.
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 -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 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.
由于长期使用皮质类固醇治疗会导致免疫抑制个体出现机会性真菌感染，从而引起高发病率和死亡率，因此我们在此研究了地塞米松（Dex）治疗对相关免疫调节的影响。我们通过高内涵筛选和流式细胞术分析发现，在单核细胞向巨噬细胞分化过程中，低至0.1µg/mL的Dex会导致巨噬细胞极化从M1型转变为M2样巨噬细胞。这种由Dex介导的巨噬细胞重极化的特征是M2标志物CD163显著上调，M1标志物CD40和CD86下调，以及表型特性和黏附性的改变。这些由Dex介导的表型改变还与通过PKM2协调的巨噬细胞代谢转换有关。经如此处理的巨噬细胞失去了阻止 萌发的能力，这与真菌生长加速、巨噬细胞破坏以及抗炎细胞因子谱的诱导相关。综上所述，皮质类固醇治疗后巨噬细胞的重极化以及随之转变为抗炎表型可能在引发侵袭性曲霉病（IA）中起重要作用，因为它抑制了对抗广泛真菌生长所需的固有免疫反应。
