地塞米松对需要辅助氧疗的COVID-19患者的生存率有所提高。虽然它的广谱免疫抑制效应已得到广泛描述，但地塞米松在COVID-19住院患者中调节的免疫机制仍有待阐明。我们结合了功能性免疫学测定和组学方法，研究了地塞米松对COVID-19患者外周血浆和单个核细胞（PBMCs）的体外和体内效应。我们从2021年2月至7月之间从一般病房中招募了符合地塞米松治疗资格的COVID-19住院患者。在开始地塞米松治疗前后进行了全血转录组学和靶向测定血浆蛋白组学分析。从健康个体和COVID-19患者中分离出PBMCs，将其在体外与灭活的SARS-CoV-2刺激下与地塞米松存在与否进行刺激，评估转录组和细胞因子反应。地塞米松有效抑制了PBMCs体外感染SARS-CoV-2诱导的化学趋化因子和细胞因子的转录和蛋白质表达。COVID-19患者地塞米松治疗导致整个血液免疫细胞中与I型和II型干扰素（IFN）信号通路相关的基因下调。此外，地塞米松减弱了与疾病严重程度和致命结果（如肿瘤坏死因子[TNF]、白细胞介素-6 [IL-6]、趋化因子配体2 [CCL2]、C-X-C趋化因子配体8 [CXCL8]和C-X-C趋化因子配体10 [CXCL10]）相关的促炎细胞因子和趋化因子的循环浓度。在COVID-19患者的PBMCs中，体外刺激多种病原体或Toll样受体（TLR）配体后，地塞米松有效抑制了细胞因子反应。我们描述了地塞米松对导致COVID-19严重表现中观察到的细胞因子高反应性通路（包括I型/II型IFN信号通路）的抗炎影响。地塞米松可能会通过在疾病早期抑制IFN反应而对轻症COVID-19患者产生不良影响，而在临床严重表型患者中表现出减弱细胞因子过强反应的有益效果。 Copyright © 2023 Engel, van der Made, Keur, Setiabudiawan, Röring, Damoraki, Dijkstra, Lemmers, Ioannou, Poulakou, van der Meer, Giamarellos-Bourboulis, Kumar, van de Veerdonk, Netea and Ziogas.

Dexamethasone improves the survival of COVID-19 patients in need of supplemental oxygen therapy. Although its broad immunosuppressive effects are well-described, the immunological mechanisms modulated by dexamethasone in patients hospitalized with COVID-19 remain to be elucidated.We combined functional immunological assays and an omics-based approach to investigate the in vitro and in vivo effects of dexamethasone in the plasma and peripheral blood mononuclear cells (PBMCs) of COVID-19 patients.Hospitalized COVID-19 patients eligible for dexamethasone therapy were recruited from the general care ward between February and July, 2021. Whole blood transcriptomic and targeted plasma proteomic analyses were performed before and after starting dexamethasone treatment. PBMCs were isolated from healthy individuals and COVID-19 patients and stimulated with inactivated SARS-CoV-2 ex vivo in the presence or absence of dexamethasone and transcriptome and cytokine responses were assessed.Dexamethasone efficiently inhibited SARS-CoV-2-induced in vitro expression of chemokines and cytokines in PBMCs at the transcriptional and protein level. Dexamethasone treatment in COVID-19 patients resulted in down-regulation of genes related to type I and II interferon (IFN) signaling in whole blood immune cells. In addition, dexamethasone attenuated circulating concentrations of secreted interferon-stimulating gene 15 (ISG15) and pro-inflammatory cytokines and chemokines correlating with disease severity and lethal outcomes, such as tumor necrosis factor (TNF), interleukin-6 (IL-6), chemokine ligand 2 (CCL2), C-X-C motif ligand 8 (CXCL8), and C-X-C motif chemokine ligand 10 (CXCL10). In PBMCs from COVID-19 patients that were stimulated ex vivo with multiple pathogens or Toll-like receptor (TLR) ligands, dexamethasone efficiently inhibited cytokine responses.We describe the anti-inflammatory impact of dexamethasone on the pathways contributing to cytokine hyperresponsiveness observed in severe manifestations of COVID-19, including type I/II IFN signaling. Dexamethasone could have adverse effects in COVID-19 patients with mild symptoms by inhibiting IFN responses in early stages of the disease, whereas it exhibits beneficial effects in patients with severe clinical phenotypes by efficiently diminishing cytokine hyperresponsiveness.Copyright © 2023 Engel, van der Made, Keur, Setiabudiawan, Röring, Damoraki, Dijkstra, Lemmers, Ioannou, Poulakou, van der Meer, Giamarellos-Bourboulis, Kumar, van de Veerdonk, Netea and Ziogas.