Systemic Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Disease, Bethesda, MD, USA.
Critical Care Medicine Department, National Institutes of Health Clinical Center, Bethesda, MD, USA.
Sci Adv. 2023 Jan 4;9(1):eade8272. doi: 10.1126/sciadv.ade8272.
Spleen tyrosine kinase (SYK) is a previously unidentified therapeutic target that inhibits neutrophil and macrophage activation in coronavirus disease 2019 (COVID-19). Fostamatinib, a SYK inhibitor, was studied in a phase 2 placebo-controlled randomized clinical trial and was associated with improvements in many secondary end points related to efficacy. Here, we used a multiomic approach to evaluate cellular and soluble immune mediator responses of patients enrolled in this trial. We demonstrated that SYK inhibition was associated with reduced neutrophil activation, increased circulation of mature neutrophils (CD10CD33), and decreased circulation of low-density granulocytes and polymorphonuclear myeloid-derived suppressor cells (HLA-DRCD33CD11b). SYK inhibition was also associated with normalization of transcriptional activity in circulating monocytes relative to healthy controls, an increase in frequency of circulating nonclassical and HLA-DR classical monocyte populations, and restoration of interferon responses. Together, these data suggest that SYK inhibition may mitigate proinflammatory myeloid cellular and soluble mediator responses thought to contribute to immunopathogenesis of severe COVID-19.
脾酪氨酸激酶 (SYK) 是一个先前未被识别的治疗靶点，可抑制 2019 年冠状病毒病 (COVID-19) 中的中性粒细胞和巨噬细胞活化。SYK 抑制剂 fostamatinib 在一项 2 期安慰剂对照随机临床试验中进行了研究，与许多与疗效相关的次要终点的改善相关。在这里，我们使用多组学方法评估了参与该试验的患者的细胞和可溶性免疫介质反应。我们证明，SYK 抑制与中性粒细胞活化减少、成熟中性粒细胞（CD10CD33）循环增加以及低密度粒细胞和多形核髓系来源抑制细胞（HLA-DRCD33CD11b）循环减少有关。SYK 抑制还与循环单核细胞相对于健康对照的转录活性正常化、循环非经典和 HLA-DR 经典单核细胞群体频率增加以及干扰素反应恢复有关。总之，这些数据表明，SYK 抑制可能减轻被认为有助于严重 COVID-19 免疫发病机制的促炎髓样细胞和可溶性介质反应。
