Welcome to our e-Learning talk. Today, we will be discussing the inflammatory role some cytokines play in the adverse effects observed in COVID-19 and what is being done to combat them.

Cytokines are small proteins, which play a significant role in intracellular signaling and the immune response. Cytokines generally are secreted by a cell and circulate in the body until they bind to a complementary receptor on the surface of another cell (or even the secreting cell itself). This leads to a response from the cell receiving the signal.
 
Cytokines are able to induce a number of responses from a cell including upregulation or downregulation of genes, innate and adaptive immune responses, or inflammation among many other processes. The immune system uses cytokines as a major means of communicating and coordinating its response to several types of disturbances.
 
In some cases, when the immune system responds too strongly, it can result in a phenomenon known as a “cytokine storm.” A cytokine storm can lead to deleterious effects in the host organism through hyperinflammation, resulting from a feedback loop of cytokines activating immune cells, which respond by producing more cytokines and attracting more immune cells to the affected tissue. COVID-19 has been shown to overwhelm a subset of infected patients through the propagation of a cytokine storm.

Several studies have investigated the levels of various cytokines in patients suffering from COVID-19. One study from Wuhan, China looked at the plasma level of several cytokines in COVID-19 patients in both the ICU and non-ICU hospitalization states and compared their cytokine levels with normal ranges. They found elevated levels of several cytokines listed in the chart you see here when compared with healthy adults. Additionally, patients in the ICU had higher levels of a subset of cytokines compared with non-ICU patients. IL-2, which is elevated in ICU patients, was not found in non-ICU COVID patients.
 
The study’s authors noted that these high levels of pro-inflammatory cytokines are hallmarks of a cytokine storm. They remarked that those patients requiring ICU treatment were the ones expressing higher levels of several of these cytokines, suggesting that it is likely correlated to disease severity in COVID-19. Of course, follow-up studies will be important to determine the role of each of these cytokines and the degree to which they affect the severity of the disease.

Of these cytokines, IL-1β and IL-6 have potent inflammatory ability, so let’s take a closer look at their role in COVID-19 patients.

Another correlation that has arisen in studying COVID-19 is that patients had a high rate of lymphopenia. Lymphopenia refers to a condition in which a person has low levels of lymphocytes in their blood. The observation of lymphopenia in conjunction with elevated levels of IL-1β has led some to suggest that perhaps cell pyroptosis is ultimately responsible for much of damage caused by SARS-CoV-2.
 
Pyroptosis refers to a specific type of cell death in which immune cells respond to pathogens by activation of inflammasomes, leading to activation and secretion of pro-inflammatory cytokines like IL-1β. During this process, the immune cells die, but the release of pro-inflammatory cytokines leads to the recruitment of additional immune cells. The process helps eliminate the intracellular pathogen by destroying its host cell. This process can quickly lead to a depletion of lymphocytes in the patient, greatly limiting their ability to fight off the virus and recover from diseases like COVID-19. This phenomenon has been documented in SARS-Associated Coronoavirus, or SARS-CoV, which has led some to suggest a similar role in the SARS-CoV-2 response.

IL-6 is an important cytokine in inflammation. IL-1β is a major activator of IL-6 expression and it can be produced by almost all stromal cells and immune system cells. In light of the elevated IL-1β levels observed in COVID-19, one additionally observes a corresponding increase in IL-6 levels. IL-6 plays various roles in the immune response that can be both anti-inflammatory and pro-inflammatory.
 
IL-6 affects several signal transduction pathways in various cell populations. Through the activation of various pathways including the JAK-STAT, RAS-RAF, SRC-YAP-NOTCH, and AKT-PI3 Kinase pathways, it is able to promote biological functions including proliferation, differentiation, and immune regulation, among others.

In these ways, IL-6 is able to promote T cell population expansion and activation, as well as B cell differentiation. IL-6 has a number of effects on T cells including promoting Th17 cell lineage and function and the development of self-reactive pro-inflammatory CD4 T cell responses. It can also inhibit the induction of Tregs that could dampen an immune response. This effect is thought to be a reason for the major deleterious effects observed in the case of cytokine storms.

Several current therapeutics approved for use in autoimmune inflammatory diseases, like rheumatoid arthritis, have been suggested as potential therapeutics for their efficacy in helping reduce inflammation in COVID-19.
 
The first drug, Tocilizumab, is a humanized antibody that targets the IL-6 receptor and is approved for treatment of rheumatoid arthritis. This blocks the ability of IL-6 to bind to its target receptor and reduces the effect of elevated IL-6 on the patient. Ultimately, this is thought to reduce the inflammation brought about in the cytokine storm, bringing the immune response under control.

A second treatment approved for rheumatoid arthritis and being explored for treating COVID-19 is Anakinra. Anakinra is a recombinant version of the IL-1 receptor antagonist. Native IL-1 receptor antagonist has the effect of blocking IL-1 from binding the IL-1 receptor and initiating downstream signaling. Similar to Tocilizumab, the thinking is that Anakinra might be another effective way of reducing inflammation and bringing the immune response into balance.
 
A third potential therapy is the JAK inhibitor, Fedratinib, which is approved for the use in patients suffering from myelofibrosis. The JAK pathway is one of several that is activated by IL-6 and blocking it may reduce inflammation by inhibiting the Th17 response described earlier.
 
While there are many treatments available targeting cytokines and hyperinflammation, it will be important to study their benefits and specific effects in COVID-19 patients as cytokines play critical roles in a number of cellular processes.

In response to SARS-CoV-2, the human body mounts a considerable immune response. Several significant cytokines are upregulated in response to the virus and lead to an oversized immune response. This response creates a feedback loop of cytokine production and secretion known as a cytokine storm.
 
Specifically, IL-1β and IL-6 have been noted to be significantly upregulated. Due to their roles in the inflammatory response, they have attracted a lot of attention from researchers looking for ways to minimize the damage to patients from COVID-19. Several currently approved treatments that target these cytokines are being suggested and investigated for their efficacy in treating the hyperinflammation that occurs in COVID-19.
 
The cytokine response is a major focus of research and therapeutics in the fight against COVID-19. Still, there is a final category of proteins that we will explore in another video: chemokines.

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