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Cytokine Storm – What is it?

Image Credit: Michigan Health Lab

Fatality among patients infected with SARS-CoV-2 can be attributed to the cytokine storm. Cytokines are proteins that serve as messengers for the immune system. Once released from a cell, they sift through the body until they reach their destination: a receptor to bind to. By binding to receptors, they are able to trigger immune responses.

A cytokine storm is the uncontrollable release of these messengers. When cytokines are secreted from cells without restraint, this can cause the immune response to go haywire—and start attacking not just infected cells, but also healthy cells.

When immune cells—like macrophages, dendritic cells, and monocytes—detect the presence of SARS-CoV-2, they understand that it is time to trigger the immune response and so secrete cytokines to recruit help to the area—the most notable cytokine being one known as IL-6.

IL-6 must bind to an IL-6 receptor in one of two ways: classic signaling or trans-signaling. Classic signaling was named after the notion that it is the age-old, well-documented form of receptor binding. IL-6 binds to an IL-6 receptor embedded in the cell membrane; for this reason, it is also called the mIL-6 receptor in the context of classic signaling—the “m” standing for membrane.

Trans-signaling was more recently observed and derives its name from the root trans—meaning that this is a process that occurs across macromolecules. In Trans-signaling, the IL-6R is no longer bound to the cell membrane; instead, it floats freely in the solution surrounding the cell—hence it is also referred to as the sIL-6R… the “s” standing for soluble. IL-6 binds to the freely floating sIL-6R, and then this IL-6/sIL-6R complex binds to a protein on the cell surface known as gp130–short for glycoprotein 130. However, there is a caveat—this IL-6/sIL-6R complex can only bind to cells that do not have a mIL-6R embedded in their cell membrane, which makes sense because the IL-6/sIL-6R complex was designed solely for gp130–not the mIL-6R.

An example of a cell this IL-6/sIL-6R complex can bind to is an endothelial cell—the cell that lines the membrane of each of our organs. They have the required gp130 setup to activate the IL-6/sIL-6R complex. Once the complex binds to gp130 on an endothelial cell, a specific cascade of events—known as a signal transduction pathway—will occur. In this specific case, trans-signaling will result in the JAK-STAT pathway being followed—short for Janus Kinase-Signal Transducer and Activator of Transcription.

This specific pathway will result in, most notably, the increased production of VEGF—short for Vascular Endothelial Growth Factor—the decreased production of E-cadherin, and the increased production of more IL-6. VEGF is a protein responsible for regulating vascular permeability—the more of it there is, the more leaky your blood vessels will become. E-cadherin has a similar effect—the less of it there is, the more vascular leakage there will be. The additional IL-6 will continue its trans-signaling and classic signaling pathways, producing more and more of VEGF, E-cadherin, and itself in an endless, uncontrollable loop—resulting in an unsafe amount of both VEGF and E-cadherin, causing your blood vessels to leak its contents into potentially life-threatening locations… like your lungs. This uncontrollable escalation is what has earned this cascade of events the title “cytokine storm.” In fact, this pneumonia-like buildup of fluid has been among the primary causes of mortality in COVID-19 patients. In these cases, it is the uncontrollably escalating immune response to SARS-CoV-2, not the virus itself that has proven deadly.

Bibliography

Anne Trafton | MIT News Office. “Proteins May Halt the Severe Cytokine Storms Seen in COVID-19 Patients.” MIT News | Massachusetts Institute of Technology, https://news.mit.edu/2020/proteins-cytokine-storms-covid-19-0416. 

Goodman, Brenda. “Cytokine Storms May Be Fueling Some Covid Deaths.” WebMD, WebMD, 17 Apr. 2020, https://www.webmd.com/lung/news/20200417/cytokine-storms-may-be-fueling-some-covid-deaths.