Interplay between interleukin-6 signaling and the vascular endothelium in cytokine storms

Abstract

Interleukin-6 (IL-6) plays a crucial role in host defense against infection and tissue injuries and is a bioindicator of multiple distinct types of cytokine storms. In this review, we present the current understanding of the diverse roles of IL-6, its receptors, and its signaling during acute severe systemic inflammation. IL-6 directly affects vascular endothelial cells, which produce several types of cytokines and chemokines and activate the coagulation cascade. Endothelial cell dysregulation, characterized by abnormal coagulation and vascular leakage, is a common complication in cytokine storms. Emerging evidence indicates that a humanized anti-IL-6 receptor antibody, tocilizumab, can effectively block IL-6 signaling and has beneficial effects in rheumatoid arthritis, juvenile systemic idiopathic arthritis, and Castleman's disease. Recent work has also demonstrated the beneficial effect of tocilizumab in chimeric antigen receptor T-cell therapy-induced cytokine storms as well as coronavirus disease 2019 (COVID-19). Here, we highlight the distinct contributions of IL-6 signaling to the pathogenesis of several types of cytokine storms and discuss potential therapeutic strategies for the management of cytokine storms, including those associated with sepsis and COVID-19.

Fig. 1. Three modes of IL-6R signaling and their associated intracellular pathways.

To activate signaling, IL-6 requires two different receptors, IL-6R and gp130. IL-6 can bind to membrane-bound IL-6R (mIL-6R, classic signaling) or soluble IL-6R (sIL-6R, trans-signaling) or be presented by T cells through mIL-6R expressed on dendritic cells (trans-presentation). In all three modes of IL-6R signaling, a hexamer complex with gp130 is formed. IL-6 binding activates two main pathways: the JAK–MAPK pathway and JAK–STAT3 pathway. A tyrosine motif in the gp130 intracellular region exerts biological activities. To eliminate gp130 signaling activation, the expression of two cytokine receptor signaling inhibitors, SOCS1 and SOCS3, is induced by IL-6 signaling. Tocilizumab, an anti-human IL-6R monoclonal antibody, inhibits all three modes of IL-6R signaling, whereas soluble gp130 (sgp130) blocks only trans-signaling as a buffer system in the blood.

Fig. 2. Modes of IL-6 activity in the acute phase of inflammation.

In the liver, IL-6 acts on hepatocytes, where it promptly induces the expression of acute-phase proteins, such as CRP, serum amyloid A, antitrypsin, hepcidin, fibrinogen, thrombopoietin, and complement 3. In blood vessels, IL-6 can directly or indirectly act on vascular endothelial cells. IL-6 increases VE–cadherin disassembly through VEGF induction and C5a receptor expression, leading to vascular permeability. IL-6 directly stimulates vascular endothelial cells to produce proinflammatory cytokines via trans-signaling. In the context of coagulation cascade activation, IL-6 increases the expression of tissue factor on monocytes to increase fibrin clot formation. During this process, thrombin can also act on vascular endothelial cells to produce the proinflammatory cytokines IL-6, IL-8, and MCP-1.

Fig. 3. Mechanism of the inflammatory process in CAR T-cell therapy-induced cytokine storm.

The activation of T cells or CAR T cells elicits the release of IFN-γ and TNF-α. These cytokines activate macrophages, subsequently inducing high levels of IL-6 production, which leads to a cytokine storm. Tocilizumab treatment can inhibit the development of a cytokine storm without blocking the cytotoxic activities of engineered T cells directed against B-cell leukemia (B-ALL).

Fig. 4. Mechanism of the inflammatory process in COVID-19-induced cytokine storm.

The pathophysiological features of COVID-19 in the lungs and vasculature are illustrated. SARS-CoV-2 infection induces a loss of vascular integrity, activation of coagulation, and amplification of inflammation through IL-6 trans-signaling. Tocilizumab may act on endothelial IL-6 trans-signaling and attenuate the symptoms of cytokine storms due to COVID-19.