Lokau Juliane, Garbers Yvonne, Vicente Manuel M, Dittrich Anna, Meltendorf Stefan, Lingel Holger, Münster-Kühnel Anja K, Brunner-Weinzierl Monika, Garbers Christoph
Institute of Clinical Biochemistry, Hannover Medical School, Hannover, Germany.
Department of Pathology, Otto-von-Guericke-University Magdeburg, Medical Faculty, Magdeburg, Germany.
Front Immunol. 2025 Jan 6;15:1488745. doi: 10.3389/fimmu.2024.1488745. eCollection 2024.
Serum levels of interleukin-6 (IL-6) are increased in COVID-19 patients. IL-6 is an effective therapeutic target in inflammatory diseases and tocilizumab, a monoclonal antibody that blocks signaling via the IL-6 receptor (IL-6R), is used to treat patients with severe COVID-19. However, the IL-6R exists in membrane-bound and soluble forms (sIL-6R), and the sIL-6R in combination with soluble glycoprotein 130 (sgp130) forms an IL-6-neutralizing buffer system capable of neutralizing small amounts of IL-6.
In this study, we analyzed serum levels of IL-6, sIL-6R and sgp130 in the serum of COVID-19 convalescent individuals with a history of mild COVID-19 disease and in acute severely ill COVID-19 patients compared to uninfected control subjects. Furthermore, we used single cell RNA sequencing data in order to determine which immune cell types are sources and targets of the individual cytokines and whether their expression is altered in severe COVID-19 patients.
We find that sIL-6R levels are not only increased in acute severely ill patients, but also in convalescents after a mild COVID-19 infection. We show that this increase in sIL-6R results in an enhanced capacity of the sIL-6R/sgp130 buffer system, but that significantly enhanced free IL-6 is still present due to an overload of the buffer. Further, we identify IL-6 serum levels, age and the number of known pre-existing medical conditions as crucial determinants of disease outcome for the patients. We also show that IL-11 has no major systemic role in COVID-19 patients and that sCD25 is only increased in acute severely ill COVID-19 patients, but not in mild convalescent individuals.
In conclusion, our study shows long-lasting alterations of the IL-6 system after COVID-19 disease, which might be relevant when applying anti-IL-6 or anti-IL-6R therapy.
新型冠状病毒肺炎（COVID-19）患者血清白细胞介素-6（IL-6）水平升高。IL-6是炎症性疾病的有效治疗靶点，托珠单抗是一种通过阻断IL-6受体（IL-6R）信号传导的单克隆抗体，用于治疗重症COVID-19患者。然而，IL-6R以膜结合形式和可溶性形式（sIL-6R）存在，sIL-6R与可溶性糖蛋白130（sgp130）结合形成一种能够中和少量IL-6的IL-6中和缓冲系统。
在本研究中，我们分析了有轻度COVID-19病史的康复个体以及急性重症COVID-19患者血清中IL-6、sIL-6R和sgp130的水平，并与未感染的对照受试者进行比较。此外，我们使用单细胞RNA测序数据来确定哪些免疫细胞类型是各细胞因子的来源和靶点，以及它们的表达在重症COVID-19患者中是否发生改变。
我们发现，sIL-6R水平不仅在急性重症患者中升高，在轻度COVID-19感染后的康复者中也升高。我们表明，sIL-6R的这种升高导致sIL-6R/sgp130缓冲系统的能力增强，但由于缓冲系统过载，仍存在显著增加的游离IL-6。此外，我们确定IL-6血清水平、年龄和已知的既往病史数量是患者疾病预后的关键决定因素。我们还表明，IL-11在COVID-19患者中没有主要的全身作用，sCD25仅在急性重症COVID-19患者中升高，而在轻度康复个体中未升高。
总之，我们的研究表明COVID-19疾病后IL-6系统存在长期改变，这在应用抗IL-6或抗IL-6R治疗时可能具有相关性。
