Cytokine storm and translating IL-6 biology into effective treatments for COVID-19

doi:10.1007/s11684-023-1044-4

Front. Med.

2023, Vol. 17

Issue (6) : 1080-1095 https://doi.org/10.1007/s11684-023-1044-4

Cytokine storm and translating IL-6 biology into effective treatments for COVID-19

Tiantian Li¹, Dongsheng Wang², Haiming Wei^3,⁴, Xiaoling Xu²(

)

¹. Department of Geriatric Medicine, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China
². Respiratory and Critical Care Medicine, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China
³. Institute of Immunology and the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Science and Medical Center, University of Science and Technology of China, Hefei 230001, China
⁴. Hefei National Laboratory for Physical Sciences at Microscale, University of Science and Technology of China, Hefei 230001, China

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Abstract

As of May 3, 2023, the coronavirus disease 2019 (COVID-19) pandemic has resulted in more than 760 million confirmed cases and over 6.9 million deaths. Several patients have developed pneumonia, which can deteriorate into acute respiratory distress syndrome. The primary etiology may be attributed to cytokine storm, which is triggered by the excessive release of proinflammatory cytokines and subsequently leads to immune dysregulation. Considering that high levels of interleukin-6 (IL-6) have been detected in several highly pathogenic coronavirus-infected diseases, such as severe acute respiratory syndrome in 2002, the Middle East respiratory syndrome in 2012, and COVID-19, the IL-6 pathway has emerged as a key in the pathogenesis of this hyperinflammatory state. Thus, we review the history of cytokine storm and the process of targeting IL-6 signaling to elucidate the pivotal role played by tocilizumab in combating COVID-19.

Keywords SARS-CoV-2 COVID-19 cytokine storm interleukin-6 tocilizumab

Corresponding Author(s): Xiaoling Xu

Just Accepted Date: 14 November 2023 Online First Date: 27 December 2023 Issue Date: 06 February 2024

Cite this article:

Tiantian Li,Dongsheng Wang,Haiming Wei, et al. Cytokine storm and translating IL-6 biology into effective treatments for COVID-19[J]. Front. Med., 2023, 17(6): 1080-1095.

URL:

https://academic.hep.com.cn/fmd/EN/10.1007/s11684-023-1044-4
https://academic.hep.com.cn/fmd/EN/Y2023/V17/I6/1080

Fig.1 Cell signaling pathways of overactivated IL-6 in COVID-19. SARS-CoV-2 infection induces the activation of diverse immune cells, including monocytes, macrophages, dendritic cells, and T cells, leading to the secretion of interleukin-6 (IL-6). IL-6 receptor (IL-6R) has two forms: membrane-bound interleukin-6 receptor (mIL-6R) and soluble interleukin-6 receptor (sIL-6R). The formation of a complex between IL-6 and mIL-6R or sIL-6R is followed by its subsequent binding to gp130 on the cell membrane. The overproduction of IL-6 initiates a cascade of signaling transduction through classic cis- and trans-signaling pathways, thereby inciting a cytokine storm and contributing to an immune disorder in severe COVID-19. As a recombinant humanized monoclonal antibody, tocilizumab can specifically target mIL-6R and sIL-6R, thereby interfering with cis- and trans-signaling pathways to block signal transduction and attenuate cytokine storm.

Fig.2 Timeline of tocilizumab from basic research discovery to clinical application in COVID-19. ^aThis article was published in the National Science Review [33]. ^bXu et al. initiated a clinical exploration and reported the benefits in PNAS [153], while registering a multicenter clinical trial (ChiCTR2000029765) to evaluate the efficacy of tocilizumab for patients with severe COVID-19. ^cAccording to Xu’s report, tocilizumab was recommended by IDSA within the context of a clinical trial [157], with 75 registered trials available on clinicaltrials.gov to date. ^dThis article was initially preprinted in medRxiv on June 30, 2021 and subsequently published in BMJ Medicine [178]. ^eThis article was published online in JAMA on July 6, 2021 [183]. IL-6, interleukin-6; NHC, National Health Commission; IDSA, Infectious Diseases Society of America; PNAS, Proceedings of the National Academy of Sciences; NIH, National Institutes of Health; NHS, National Health Service; FDA, Food and Drug Administration; NMA, network meta-analysis; PMA, prospective meta-analysis; WHO, World Health Organization; JAMA, Journal of the American Medical Association.

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