Cytokine Storm

Cytokine storm refers to the overactivation of the immune system in response to an infection, leading to excessive or uncontrolled release of proinflammatory cytokines. Cytokine storm has been reported in response to infection with cytomegalovirus, influenza virus, group A streptococcus and coronaviruses, such as SARS-CoV, SARS-CoV-2 and MERS. In COVID-19, increasing cytokine levels correlate with high viral load, respiratory distress and pulmonary damage. Often used interchangeably with cytokine release syndrome (CRS), a form of systemic inflammatory response syndrome, cytokine storm is characterized as an immediate onset of CRS.

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Pathways (3)

What are Cytokines?

Cytokines are small proteins secreted by immune cells for the purpose of communication and coordinating the body's response to infection and trigger inflammation. A cytokine response is a series of overlapping signaling networks, with redundancies and alternative pathways. An individual cytokine may have multiple, and sometimes unrelated, functions depending on the target cell and the presence/absence of other cytokines. The cytokine family includes chemokines, interferons, interleukins, colony-stimulating factors and tumor necrosis factor.

Cytokine Storm in COVID-19

Infection by SARS-CoV-2 and cytokine storm in the lungs during COVID-19 lead to acute lung injury, characterized by a mononuclear/neutrophilic inflammatory response followed by a chronic fibroproliferative phase. In the acute phase of cytokine storm, levels of acute/early response cytokines, including the cytokines TNF-α, interleukin (IL)-1β and IL-6 and the chemokines CXCL10 and CCL2, dramatically increase. The large-scale release of these factors causes and maintains an aberrant systemic immune response. Pulmonary inflammation spills over into the systemic circulation, producing persistent hypotension, hypothermia and leucocytosis, which characterize sepsis. This leads to acute respiratory distress syndrome (ARDS) and increased risk of multi-organ failure.

Mediators of the Cytokine Storm

Mediators of the Cytokine Storm and Associated Phenotypes

Figure 1: Schematic highlighting key inflammatory mediators implicated in COVID-19 cytokine storm and associated outcomes. The figure outlines the chain of events and the functional roles of key cytokines and chemokines and their cognate receptors in the development of the main clinical outcomes associated with the cytokine storm. Adapted from Tisoncik et al. (2012) Microbiol Mol Biol Rev 76 16. PMID: 22390970.

IL-6 is an important mediator of the cytokine storm. It is released by monocytes, macrophages and dendritic cells in response to coronavirus infection, and elevated serum IL-6 levels are associated with poor outcomes in COVID-19. IL-6 signals through two types of receptor, a membrane bound receptor (mIL-6R), expressed on cells of the immune system, and a soluble form (sIL-6R). Following binding of IL-6, the receptors form a complex with gp130, a ubiquitously expressed membrane protein, triggering signaling via JAK and STAT. Binding of IL-6 to mIL-6R has multiple effects on the immune system, while binding to sIL-6R can activate non-immune cells expressing gp130, such as endothelial cells. IL-6-induced activation of endothelial cells triggers the release of vascular endothelial growth factor (VEGF) and other cytokines, further amplifying the cytokine storm and resulting in systemic effects, such as vascular leakage, which contributes to pulmonary dysfunction.

The cytokine storm phenotype also involves hyperactivation of NF-κB signaling pathways by the action of proinflammatory cytokines at their receptors. NF-κB is a transcription factor that regulates the expression of multiple genes, including those for proinflammatory cytokines providing a positive feedback loop. It also regulates the activation, differentiation and effector functions of inflammatory T-cells, and there is evidence that it regulates the activation of inflammasomes.

NF-κB signaling is also activated by the Angiotensin II (Ang II)- Angiotensin receptor 1 (AT1) axis and in an animal model of SARS-CoV infection, AT1 receptor blockers prevent ARDS. Following viral cell entry, ACE2 is taken into the cell with SARS-CoV, resulting in an increase in serum Ang II and activation of AT1 receptors. Activation of AT2 receptors has been shown to oppose AT1 signaling with anti-inflammatory properties in some tissues, although the exact mechanism is poorly understood.

Overproduction of cytokines also leads to activation of anticoagulation pathways in COVID-19. Pathways that control thrombin and coagulation homeostasis are dysregulated by inflammation, resulting in the activation of protease-activated receptor 1 (PAR-1) by thrombin. PAR-1 mediates thrombin-induced platelet aggregation as well as cross-talk between coagulation, inflammation and fibrosis; all features of fibroproliferative lung disorders such as COVID-19.

Cytokine Storm as a Therapeutic Target

As a therapeutic target in COVID-19, cytokine storm is problematic, as treatment with immunomodulators or anti-cytokine therapies, for example, must strike a balance between reducing the overactive immune response and ensuring maintenance of adequate response for pathogen clearance. Dexamethasone (Cat. No. 1126), a widely used synthetic glucocorticoid, has been shown to reduce deaths by a third in patients hospitalized with COVID-19 in the RECOVERY (Randomised Evaluation of COVid-19 thERapY) study, likely via suppression of cytokines. It was the first medicine to show life-saving efficacy in patients infected with COVID-19.

Other approved medicines being repurposed to suppress the cytokine storm include JAK inhibitors, such as Baricitinib (Cat. No. 7222) which is used as a treatment for rheumatoid arthritis.

Find out more about Simple Plex for COVID-19 Cytokine Storm profiling

Pathways for Cytokine Storm

MAPK Signaling Pathway

MAPK Signaling Pathway

The mitogen-activated protein kinase pathway evokes an intracellular signaling cascade in response to extracellular stimuli such as heat and stress. It can influence cell division, metabolism and survival.
NF-κB Signaling Pathway

NF-κB Signaling Pathway

NF-κB signaling plays an important role in inflammation, the innate and adaptive immune response and stress. Dysregulated signaling can occur in inflammatory and autoimmune diseases.
Toll-like Receptor Signaling Pathway

Toll-like Receptor Signaling Pathway

TLR signaling is involved in the cellular response to threatening molecules such as bacteria and viruses. It results in an inflammatory and immmunological response.