Dexamethasone modulates immature neutrophils and interferon programming in severe COVID-19

While critical for host defense, innate immune cells are also pathologic drivers of acute respiratory distress syndrome (ARDS). Innate immune dynamics during COVID-19 ARDS, compared to ARDS from other respiratory pathogens, is unclear. Moreover, mechanisms underlying beneficial effects of dexamethasone during severe COVID-19 remain elusive. Using scRNA-seq and plasma proteomics, we discovered that compared to bacterial ARDS, COVID-19 was associated with distinct neutrophil polarization characterized by interferon (IFN) and prostaglandin (PG) active states. Dexamethasone during severe COVID-19 depleted circulating neutrophils, altered IFN^active neutrophils, downregulated interferon-stimulated gene, and activated IL1R2^+ve neutrophils. Dexamethasone also expanded immature neutrophils expressing immunosuppressive molecules and remodeled cellular interactions by changing neutrophils from information receivers into information providers. Male patients had higher proportions of IFN^active neutrophils, preferential steroid-induced immature neutrophil expansion, and possibly different effects on outcome. Our single-cell atlas (www.biernaskielab.ca/COVID_neutrophil) defines COVID-19-enriched neutrophil states and molecular mechanisms of dexamethasone action to develop targeted immunotherapies for severe COVID-19.<br>

固有免疫细胞（innate immune cells）不仅在宿主防御中发挥关键作用，同时也是急性呼吸窘迫综合征（acute respiratory distress syndrome, ARDS）的病理性驱动因素。相较于其他呼吸道病原体引发的ARDS，新型冠状病毒感染相关ARDS（COVID-19 ARDS）中的固有免疫动态变化尚不明确。此外，地塞米松（dexamethasone）在重型新型冠状病毒感染中产生有益作用的潜在分子机制仍有待阐明。本研究借助单细胞RNA测序（scRNA-seq）与血浆蛋白质组学技术，发现相较于细菌性ARDS，新冠病毒感染呈现出以干扰素（IFN）和前列腺素（PG）活化状态为特征的独特中性粒细胞极化模式。重型新冠感染患者接受地塞米松治疗后，循环中性粒细胞数量减少，IFN活化型中性粒细胞的特征发生改变，干扰素刺激基因表达下调，同时激活IL1R2阳性（IL1R2^+ve）中性粒细胞。地塞米松还可扩增表达免疫抑制分子的未成熟中性粒细胞，并通过将中性粒细胞从信息接收者转变为信息提供者，重塑细胞间互作网络。男性患者体内IFN活化型中性粒细胞比例更高，糖皮质激素诱导的未成熟中性粒细胞扩增更为显著，且其治疗结局可能受到的药物影响存在差异。本研究构建的单细胞图谱（www.biernaskielab.ca/COVID_neutrophil）明确了新冠病毒感染富集的中性粒细胞状态，以及地塞米松的作用分子机制，可为重型新冠感染的靶向免疫治疗提供理论依据。