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ORIGINAL RESEARCH article

Front. Immunol.
Sec. Cytokines and Soluble Mediators in Immunity
Volume 15 - 2024 | doi: 10.3389/fimmu.2024.1488745

Long-term increase in soluble interleukin-6 receptor levels in convalescents after mild COVID-19 infection

Provisionally accepted
Juliane Lokau Juliane Lokau 1Yvonne Garbers Yvonne Garbers 2Manuel M Vicente Manuel M Vicente 1Anna Dittrich Anna Dittrich 3Stefan Meltendorf Stefan Meltendorf 3Holger Lingel Holger Lingel 3Anja Münster-Kühnel Anja Münster-Kühnel 1Monika C. Brunner-Weinzierl Monika C. Brunner-Weinzierl 3Christoph Garbers Christoph Garbers 1*
  • 1 Institute of Clinical Biochemistry, Hannover Medical School, Hannover, Germany
  • 2 Osnabrück University of Applied Sciences, Osnabrück, Lower Saxony, Germany
  • 3 Otto von Guericke University Magdeburg, Magdeburg, Saxony-Anhalt, Germany

The final, formatted version of the article will be published soon.

    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. 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. 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 expression of these cytokines is altered in severe COVID-19 patients. 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.

    Keywords: Interleukin-6, interleukin-6 receptor, gp130, COVID-19, sCD25

    Received: 30 Aug 2024; Accepted: 12 Dec 2024.

    Copyright: © 2024 Lokau, Garbers, Vicente, Dittrich, Meltendorf, Lingel, Münster-Kühnel, Brunner-Weinzierl and Garbers. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Christoph Garbers, Institute of Clinical Biochemistry, Hannover Medical School, Hannover, Germany

    Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.