Department Inserm, UMR_S 1256 Nutrition-Genetics-Environmental Risk Exposure, Université de Lorraine and University Regional hospital of Nancy, Nancy, France.
Center for CardioVascular and Nutrition Research (RG, JF), INSERM, INRA and Aix-Marseille University, Marseille, France.
Allergy. 2021 Jun;76(6):1846-1858. doi: 10.1111/all.14746. Epub 2021 Feb 27.
Many arguments suggest that neutrophils could play a prominent role in COVID-19. However, the role of key components of neutrophil innate immunity in severe forms of COVID-19 has deserved insufficient attention. We aimed to evaluate the involvement of neutrophil elastase, histone-DNA, and DNases in systemic and multi-organ manifestations of COVID-19.
We performed a multicenter study of markers of neutrophil innate immunity in 155 cases consecutively recruited in a screening center, local hospitals, and two regional university hospitals. The cases were evaluated according to clinical and biological markers of severity and multi-organ manifestations and compared to 35 healthy controls.
Blood neutrophil elastase, histone-DNA, myeloperoxidase-DNA, and free dsDNA were dramatically increased, and DNase activity was decreased by 10-fold, compared with controls. Neutrophil elastase and histone-DNA were associated with intensive care admission, body temperature, lung damage, and markers of cardiovascular outcomes, renal failure, and increased interleukin-6 (IL-6), IL-8, and CXCR2. Neutrophil elastase was an independent predictor of the computed tomography score of COVID-19 lung damage and the number of affected organs, in multivariate analyses. The increased blood concentrations of NE and neutrophil extracellular traps were related to exacerbation of neutrophil stimulation through IL-8 and CXCR2 increased concentrations and increased serum DAMPs, and to impaired degradation of NETs as a consequence of the dramatic decrease in blood DNase activity.
Our results point out the key role of neutrophil innate immunity exacerbation in COVID-19. Neutrophil elastase and DNase could be potential biomarkers and therapeutic targets of severe systemic manifestations of COVID-19.
许多观点认为中性粒细胞可能在 COVID-19 中发挥重要作用。然而，中性粒细胞固有免疫的关键成分在 COVID-19 严重形式中的作用尚未得到充分关注。我们旨在评估中性粒细胞弹性蛋白酶、组蛋白-DNA 和 DNase 在 COVID-19 全身和多器官表现中的作用。
我们在一个筛选中心、当地医院和两家地区大学医院连续招募了 155 例患者，进行了中性粒细胞固有免疫标志物的多中心研究。根据严重程度和多器官表现的临床和生物学标志物对病例进行评估，并与 35 名健康对照进行比较。
与对照组相比，血液中性粒细胞弹性蛋白酶、组蛋白-DNA、髓过氧化物酶-DNA 和游离 dsDNA 显著增加，而 DNase 活性降低 10 倍。中性粒细胞弹性蛋白酶和组蛋白-DNA 与入住重症监护病房、体温、肺部损伤以及心血管结局、肾衰竭和白细胞介素-6（IL-6）、白细胞介素-8（IL-8）和 CXCR2 标志物相关。在多变量分析中，中性粒细胞弹性蛋白酶是 COVID-19 肺部损伤和受累器官数量的 CT 评分的独立预测因子。血液中 NE 和中性粒细胞胞外陷阱浓度的增加与通过增加的 IL-8 和 CXCR2 浓度以及增加的血清 DAMPs 加剧中性粒细胞刺激以及由于血液 DNase 活性的急剧下降而导致 NETs 降解受损有关。
我们的研究结果指出了中性粒细胞固有免疫加剧在 COVID-19 中的关键作用。中性粒细胞弹性蛋白酶和 DNase 可能是 COVID-19 严重全身表现的潜在生物标志物和治疗靶点。
