The bio-mission of interleukin-6 in the pathogenesis of COVID-19: A brief look at potential therapeutic tactics

Abstract

Interleukin-6 (IL-6), known as an inflammatory cytokine, can be involved in many innate and adaptive immune responses. The role of IL-6 in the pathogenesis of the novel coronavirus disease 2019 (COVID-19) has recently received much more attention due to the spread of the virus and its pandemic potential. Cytokine storm is among the most critical pathological events in patients affected with coronaviruses (CoVs), i.e., severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV), and COVID-19, causing inflammation-induced lung injury and also occurring as a result of dysregulation of immune responses to the mentioned viruses. IL-6, along with some other inflammatory cytokines, including IL-1 beta (β), IL-8, and tumor necrosis factor-alpha (TNF-α), as well as inflammatory chemokines, can significantly contribute to, fever, lymphopenia, coagulation, lung injury, and multi-organ failure (MOF). Therefore, researchers are to explore novel approaches to treat the disease through targeting of IL-6 and its receptors based on prior experience of other disorders. In this review article, the latest findings on the role of IL-6 in the pathogenesis of COVID-19, as well as therapeutic perspectives, were summarized and discussed.

Keywords: COVID-19; Cytokine storm; Immunopathogenesis; Interleukin-6; SARS-CoV-2.

Graphical abstract

Fig. 1

IL-6 signaling pathways. Three possible signaling pathways are initiated following the activation of JAK with the hexameric complex (i.e., two IL-6/IL-6R/gp130 heterodimers), including STAT3, MAPK, and PI3K, PKB pathways as well as NF-кB. Stimulation of PKB/Akt, MAPK, STAT3, and NF-кB prompt expression of a wide range of inflammatory and anti-inflammatory cytokines as well as transcription factors. JAK; Janus kinase, STAT3; signal transducer and transcription-3, MAPK; mitogen-activated protein kinases, PI3K; phosphoinositol-3 kinase, PKB; protein kinase B (also known as Akt), NF-кB nuclear factor-κB, P; phosphor, Ikk; IκB kinase, mTOR; mammalian target of rapamycin, GRB2; growth factor receptor-bound protein 2.

Fig. 2

Role of IL-6 in the pathogenesis of COVID-19 and possible therapeutic approaches. SARS-CoV-2 enters the human body mainly through the nose, eyes, and mouth, it enters the host cell (mainly alveolar type 2 cells) through attachment to its receptors (ACE2, CD147, DC-SIGN, L-SIGN) and stimulates inflammatory and antiviral responses through the production and secretion of cytokines and inflammatory cytokines such as IL-6. Sometimes dysregulated inflammatory responses can cause a cytokine storm, ARDS, and multi-organ failure or even death. On the other hand, it may be possible to use IL-6/IL-6R inhibitors in the treatment of patients with COVID-19. SARS-CoV-2; severe acute respiratory syndrome coronavirus 2, ss RNA; single strain RNA, ACE2; angiotensin-converting enzyme 2, DC-SIGN; dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin, TLR; toll-like receptor, RIG-I; retinoic acid-inducible gene-I, MAVS; mitochondrial anti-viral-signaling protein, MDA-5; melanoma differentiation-associated protein 5, NFκB; nuclear factor kappa-light-chain-enhancer of activated B cells, PAF; platelet-activating factor, LT; leukotriene, ROS; reactive oxygen spices, CRP; c-reactive protein, MQ; macrophage, TNF-α; tumor necrosis factor-alpha, IFN-I; interferon type I, IL-6; interleukin-6, IL-6R; interleukin-6 receptor ARDS; acute respiratory distress syndrome.