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Review
. 2020 Sep;146(3):518-534.e1.
doi: 10.1016/j.jaci.2020.07.001.

The role of IL-6 and other mediators in the cytokine storm associated with SARS-CoV-2 infection

Ana Copaescu  1 , Olivia Smibert  2 , Andrew Gibson  3 , Elizabeth J Phillips  4 , Jason A Trubiano  5
Affiliations
Review

The role of IL-6 and other mediators in the cytokine storm associated with SARS-CoV-2 infection

Ana Copaescu et al. J Allergy Clin Immunol. 2020 Sep.

Abstract

The coronavirus disease 2019 pandemic caused by severe acute respiratory syndrome coronavirus 2 presents with a spectrum of clinical manifestations from asymptomatic or mild, self-limited constitutional symptoms to a hyperinflammatory state ("cytokine storm") followed by acute respiratory distress syndrome and death. The objective of this study was to provide an evidence-based review of the associated pathways and potential treatment of the hyperinflammatory state associated with severe acute respiratory syndrome coronavirus 2 infection. Dysregulated immune responses have been reported to occur in a smaller subset of those infected with severe acute respiratory syndrome coronavirus 2, leading to clinical deterioration 7 to 10 days after initial presentation. A hyperinflammatory state referred to as cytokine storm in its severest form has been marked by elevation of IL-6, IL-10, TNF-α, and other cytokines and severe CD4+ and CD8+ T-cell lymphopenia and coagulopathy. Recognition of at-risk patients could permit early institution of aggressive intensive care and antiviral and immune treatment to reduce the complications related to this proinflammatory state. Several reports and ongoing clinical trials provide hope that available immunomodulatory therapies could have therapeutic potential in these severe cases. This review highlights our current state of knowledge of immune mechanisms and targeted immunomodulatory treatment options for the current coronavirus disease 2019 pandemic.

Keywords: COVID-19; IL-6; JAK; SARS-CoV-2; STING; TNF-α; cytokine storm; cytokines; hemophagocytic lymphohistiocytosis; hyperinflammatory; proinflammatory; sepsis.

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Figures

Fig 1
Fig 1
COVID-19 immunologic mechanisms for CS and the possible role of biologics. When SARS-CoV-2 PAMPs and/or DAMPs bind to TLRs on the surface of resident alveolar macrophages, they become activated and secrete TNF, IL-1β, and IL-6. In increased levels, these cytokines will be the hallmark of the CS responsible for the ARDS and CS in COVID-19. The different targets of biologics are illustrated in the figure. Specifically, the downstream effect of IL-6 can be blocked with tocilizumab, sarilumab, or siltuximab and the effects of IL-1β with anakinra or canakinumab. CD8+ T cells produce IFN-γ, causing direct tissue damage, whereas activated CD4+ T cells, in the presence of transforming growth factor β and IL-6, will differentiate into the TH17-cell subset, responsible for secreting IL-17A and IL-17F, which, among numerous roles, target macrophages, dendritic cells, endothelial cells, and fibroblasts to increase the production of IL-1, IL-6, and TNF. DAMP, Damage-associated molecular pattern; PAMP, pathogen-associated molecular pattern; TLR, Toll-like receptor; TMPRSS2, transmembrane protease, serine 2.
Fig 2
Fig 2
The implications of the STING pathway in coronavirus. The cGAS-STING pathway is activated by sensing foreign cytosolic DNA (obtained after reverse transcription from SARS-CoV-2). cGAS catalyzes the generation of cyclic GMP-AMP (cGAMP), which binds and activates STING in the ER, leading to the expression of IFNs and other cytokines. IL-1β is produced after the NLRP3 inflammasome, activated by AIM2-sensing foreign DNA, induces the formation of caspase-1, which will cleave pro–IL-1β into IL-1β. AIM2, Absent in melanoma 2; AMP, adenosine monophosphate; cGAMP, cyclic GMP-AMP; cGAS, cyclic GMP-AMP synthetase; dsDNA, double-stranded DNA; GMP, guanosine monophosphate; GTP, guanosine triphosphate; ER, endoplasmic reticulum; NLRP3, nucleotide-binding and oligomerization domain–, leucine-rich repeats–, and pyrin domain–containing protein 3.
Fig 3
Fig 3
Classic and trans-signaling IL-6R. A and B, Different signaling pathways stimulated by IL-6. Binding of IL-6 to the membrane-bound or soluble IL-6 receptor (IL-6R) leads to gp130 dimerization and JAK 1–STAT 3 signaling and activation, leading to gene expression of inflammatory cytokines. This pathway is represented only in Fig 3, A, and replaced by the word “SIGNAL” in Fig 3, B. A, Classic signaling, which is restricted to several cell types, is initiated through binding of IL-6 to the membrane IL-6R and forms a complex with gp130. B, Trans-signaling is driven by IL-6 in all gp130-expressing cells. Proinflammatory functions have been found to be mediated through binding of soluble IL-6R shredded from cells undergoing ADAM17-mediated apoptosis. C and D, IL-6 blockade therapy using a humanized anti–IL-6R mAb. A humanized anti–IL-6R antibody blocks IL-6–mediated signaling pathway by inhibiting IL-6 binding to the membrane (Fig 3, C) and soluble (Fig 3, D) receptors. ADAM17, A disintegrin and metalloprotease family protein; gp130, glycoprotein 130; IL-6R, IL-6 receptor; sIL-6R, soluble IL-6R; STAT, signal transducer and activator of transcription.
Fig E1
Fig E1
“Cytokine Storm” in PubMed Search (1985-May 2020). The figure represents the number of articles entered in PubMed from 1985 to May 2020. This marks several events that have led to CS including the 1985 original description in graft-versus-host disease, a small increase during the 2003-2005 SARS-CoV, a more significant number for the 2009-2010 H1N109, and the ongoing rise in publications associated with SARS-CoV-2.
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References

    1. Zhou F., Yu T., Du R., Fan G., Liu Y., Liu Z., et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020;395:1054–1062. - PMC - PubMed
    1. Huang C., Wang Y., Li X., Ren L., Zhao J., Hu Y., et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395:497–506. - PMC - PubMed
    1. Wu C., Chen X., Cai Y., Xia J., Zhou X., Xu S., et al. Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan, China. JAMA Intern Med. 2020;180:1–11. - PMC - PubMed
    1. Herold T, Jurinovic V, Arnreich C, Hellmuth J, von Bergwelt-Baildon M, Klein M, et al. Level of IL-6 predicts respiratory failure in hospitalized symptomatic COVID-19 patients [published online ahead of print April 10, 2020]. medRxiv. 10.1101/2020.04.01.20047381. - DOI
    1. Chen G., Wu D., Guo W.Z., Cao Y., Huang D., Wang H., et al. Clinical and immunologic features in severe and moderate coronavirus disease 2019. J Clin Investig. 2020;130:2620–2629. - PMC - PubMed