The pro-inflammatory cytokines in COVID-19 pathogenesis: What goes wrong?

Abstract

The outbreak of coronavirus disease 2019 (COVID-19), caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection, has emerged in China in December 2019 and rapidly spread to more than 196 countries worldwide. The physiopathology of human SARS-CoV-2 has not been completely understood, but its pathogenesis has been linked to a disproportionate response of the immune system. Just as described for SARS and MERS, an uncontrolled systemic inflammatory response, known as cytokine release syndrome (CRS) was observed in severe COVID-19 patients. It results from the release by immune and non-immune effector cells of substantial amounts of pro-inflammatory cytokines and appears to contribute to SARS-CoV-2 pulmonary inflammation and extensive lung damage. In addition, hyper-coagulation and thrombosis resulted from the important release of pro-inflammatory cytokines contribute to the lethality of subjects severely infected with SARS-CoV-2. It is therefore essential to have a deep understanding of the various cytokines involved in this exacerbated immune response, and that could be targeted by potential immunological treatments. The aim of this review was to gather the current knowledge about the role of pro-inflammatory cytokines, namely IL-1β, IL-6, IL-8, IL-17 and TNFα in SARS-CoV-2 CRS, the probable causes and clinical outcomes of this phenomenon in severe cases of COVID-19.

Keywords: COVID-19; Cytokines; Inflammation; SARS-CoV-2.

Fig. 1

The cytokine release syndrome and clinical outcomes in COVID-19 Pathogenesis. Numerous pro-inflammatory cytokines including TNF-α, IL-17, IL-6, IL-8 and IL-1β participate to the CRS onset. These cytokines are secreted by numerous cells like epithelial cells, macrophages, T lymphocytes, neutrophils, and Th17 cells, and exacerbate the SARS-CoV-2 infection. The excessive cytokine release has tremendous consequences such as acute lung injuries, cellular damage, microbiota alteration, severe lymphopenia and a decrease in regulatory T cells.

Fig. 2

Potential signaling pathways involved in COVID-19 cytokine release syndrome. SARS-Cov-2 binds to ACE2 receptor and activates many signaling pathways promoting inflammatory cytokine production. The IL-6 release is initiated by viral proteins, which leads to the transcription factor NF-κβ activation (green arrows). The interaction of IL-6/sIL-6R complex with gp130 protein induces many intracellular signaling pathways, including the Janus kinase (JAK)/(STAT) and (PI3K) leading to pro-inflammatory cytokines release (purple arrows). The phosphorylation of NF-κβ inhibitor proteins (IκB) results in the P65 and P50 proteins release and translocation to the nucleus, inducing NF-κβ transcription and TNFα production (orange arrows). The E protein and ORF3a viral protein activates the NLRP3 inflammasome, which generates IL-1β release (red arrows). The association of the IL-1β, IL-23, IL-6 and TGB-β induce the transcription of RORγt, leading to the differentiation of TCD4+ cells into TH-17 and IL-17 release. The hypoxia can also favor this differentiation. The activation of JNK, P38 or ERK proteins induces the activation and translocation of AP-1 on IL-8 promoter, leading to IL-8 production (blue arrows). Both cytokines IL-8 and IL-17 act by attracting neutrophils to the infectious site. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)

Fig. 3

Potential causes of COVID-19 cytokine release syndrome. Several factors or pathways may lead to the induction of CRS. For example, the direct rapid replication of the virus inside the organism, the down-regulation of INF type I and III, the down-regulation and loss of the receptor ACE2, non-neutralizing antibodies which are produced by B cells can exacerbate COVID19 through antibody-dependent enhancement (ADE), the alteration or decrease in microbiota, and also the activation of coagulation pathways. Moreover, there are some hypotheses surrounding other mechanisms that may also lead to CRS, like the action of pyroptosis due to the activation of the inflammasome or the Super Antigens (SAgs).