Cytokines - What Are They, and How Do They Relate To Inflammation?

If you get injured or have an infection, inflammation is first. When you injure yourself or get an infection, your body responds by increasing blood flow to the affected area and producing swelling or inflammation.

The process involves several immune cells that kill the invading pathogen. The core of the reaction is cytokines, which are vital in the body's immune system. Understanding how these cells work is essential. But so is answering the question, what is a cytokine?

What Are Cytokines?

Cytokines are small proteins that signal the immune system to do its job. They consist of lymphokines, monokines, chemokines, and interleukins. Cytokines can be pro-inflammatory or anti-inflammatory. 

The immune system maintains a hemostatic balance by maintaining normal cytokine levels. This way, the system avoids a hyperinflammatory response.

Cytokines and Inflammation

The inflammatory response involves the swelling, redness, heating, and inflammation of the wound. This phase can last up to two weeks in acute injuries. 

The main cells that take part in this process include:

Neutrophils

Neutrophils are white blood cells that engulf and ingest pathogens. These cells produce a network of fibers that increase cytokine production during the storm. The fibers also help in thrombi formation. 

Neutrophils express many pro-inflammatory cytokines and active antimicrobial substances like cationic peptides. Patients with cytokine storms may have hemophagocytic macrophages in the bone marrow. The cells migrate to the wound/infected site to clean up the tissue and kill the invading agents.

Macrophages

Activated monocytes differentiated into macrophages. Macrophages are also white blood cells that surround and kill pathogens. They also produce cytokines and pro-angiogenic inflammatory factors. They are tissue-resident and derive from circulating monocytes. 

During a cytokine storm, the cells activate and secrete excess cytokines. Patients with cytokine storms may have hemophagocytic macrophages in the bone marrow. This condition may cause cytopenia, characterized by lower-than-normal red blood cells.

Natural Killer Cells

Natural killer (NK) cells are cytotoxic white blood cells that kill infected cells. Inflammation causes phagocytes and natural killer cells to migrate to the infected site. The cells identify pathogens using lipopolysaccharides and ribonucleic acid pattern recognition. 

The function of NK cells decreases in a cytokine storm. It causes prolonged antigenic stimulation. As a result, it becomes harder to resolve inflammation.

The adaptive immune system also participates in cytokine production. This system consists of T cells and B cells. T cells attack specific antigens. The cells differentiate into various subsets that take part in cytokine production. B cells do not take part in cytokine production. But, these cells help treat cytokine storm disorders.

What Is A Cytokine Storm?

A cytokine storm is an immune response in which the body produces and releases excess cytokines into the blood. The condition encompasses various immune dysregulation disorders. Often, these conditions involve systemic inflammation and multiorgan dysfunction. 

Patients with cytokine storms can be febrile. In severe cases, they also experience high-grade fever. Other symptoms include diarrhea, myalgia, anorexia, fatigue, headache, and rush.

 A cytokine storm causes tissue damage and acute-phase physiological changes in internal organs. Its manifestations also overlap and converge. If not treated, a cytokine storm can progress to disseminated intravascular coagulation. 

The effect means that a patient with cytokine storm can develop:

• Vascular occlusion
• Hypoxemia
• Vasodilatory shock
• Hypotension

Cytokine storms can also cause hemostatic imbalance and death. Patients may suffer from renal failure, cholestasis, and cardiomyopathy in severe cases. Hyperinflammation, coagulopathy, and low platelet count also pose a high risk for bleeding.

What Causes A Cytokine Storm?

The immune system is the body's first line of defense against foreign invaders. When injured or infected, the system recognizes and attacks the pathogen. This response begins with the inflammatory phase. In some cases, the body produces and releases excess cytokines, a cytokine storm. The excessive production of cytokines is harmful to organ tissues.

Reasons for a Cytokine Storm

Latrogenic Cytokine Storm

Genetically engineered chimeric antigen receptor (CAR) T cells induce cytokine storms through excessive interferon-γ and interleukin-6 production. But, this effect is manageable using interleukin-6 and interleukin-1 blockade. Tumor lysis can also contribute to cytokine storms. In this case, the lysis induces pyroptosis in the targeted cells.

Pathogen-Induced Cytokine Storm

Cytokine storms occur when a pathogen invades the body. Such infections involve an immune response that induces excessive cytokine production. The reaction causes collateral damage that includes:

• Fever
• Cell death
• Coagulopathies
• Multiorgan dysfunction

For instance, Staphylococcus aureus can produce superantigens that cross-link the immune cell receptors. The result causes increased cytokine production. The bacteria also have the polyclonal activation of T cells and lead to shock or death. Pathogen-induced cytokine storms result from hyperinflammatory immune responses.

Monogenic or Autoimmune Cytokine Storm

Monogenic and autoimmune cytokine storms are rare. Autosomal recessive monogenic disorders cause cytokine storms in granule-mediated cytotoxicity through pathologic mutations. 

Autoimmune diseases cause cytokine storms in altered genes through heterozygous polymorphisms. Both monogenic and autoimmune cytokine storms involve an increase in interferon-γ production.

COVID-19-Associated Cytokine Storm

COVID-19 is a communicable disease. It first came to light in Wuhan, China, in December 2019. So far, it has affected over 375 million globally since its onset. As of March 7, 2022, 6,022,552 people died after contracting the disease. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes COVID-19. 

The disease's symptoms include:

• Shortness of breath
• Fatigue
• Fever
• Nausea
• Loss of taste or smell
• Sore throat

COVID-19 manifests as a respiratory illness in many patients and can require intensive care. COVID-19-induced cytokine storm causes progressive pulmonary thrombosis in the lungs. The storm also disseminates intravascular coagulation, causing the eventual impairment of lung function. 

The increased cytokine production damages tissues with high Angiotensin-Converting Enzyme 2 (ACE-2) concentration. These damages include:

• Plasma leakage
• Vascular permeability
• Disseminated vascular coagulation
• Massive tissue destruction

ACE-2 is highly present in the lungs and cardiovascular system. The enzyme acts as a SARS-CoV-2 receptor. 

It plays a crucial role in COVID-19-related immunity, inflammation, and cardiovascular diseases. ACE-2 protects the vascular tissues and endothelia. It also balances angiotensin II effects and acts as a cardiac biomarker. 

The immune system responds to COVID-19 by destroying SARS-CoV-2 infected cells. The endocytosis of the virus causes the loss of ACE-2 mediated cardiovascular protection. This increases myocardial fibrosis and causes cytokine storms in COVID-19 patients. 

Some therapeutic factors to consider when treating COVID-19 patients include:

1. The primary infection site influences the immune responses. The site also determines the underlying mechanisms of a cytokine storm. Meaning treatments that might be effective in some diseases might not work in others.
2.  Lymphopenia is common in COVID-19 but not cytokine storm disorders. The relation between the two conditions is still unclear.

How to Naturally Calm Cytokine Storm

You can also change your lifestyle and diet to calm the cytokine storm. Plants contain natural immunosuppressant compounds like piperine, which inhibit the production of cytokines. The compounds alter the signal pathways involved in cytokine production and release. This way, fewer cytokines reach the blood.

Fruits and vegetables also contain antioxidants and minerals that can cause anti-inflammatory effects. Likewise, fish and fish oils contain omega-3 polyunsaturated fatty acids that induce anti-inflammatory responses through various cellular membranes.

Developing a regular sleeping schedule might also calm a cytokine storm. Sleep deprivation, overeating, excessive alcohol consumption, and stress increase the production of inflammasomes like NF-kappa B. This response, in turn, increases cytokine production.

The best way to calm your cytokine storm is by identifying its symptoms before it becomes severe. This way, you can know what caused it and how to treat it. But it won't also hurt to consume more plants. After all, they have natural immunosuppressant compounds.

Also, using Probiotic Blends can help build gut health and a strong digestive system. They can also improve inflammatory response to cytokine activation, and strengthen your body’s overall ability to ward off inflammatory conditions.

Clear Probiotics proudly offers Clear Inflammatory Response with 2 targeted probiotic strains, premium prebiotics, turkey tail mushroom, and ginger root to support great gut health, and in turn help your body keep inflammation, and cytokine storms, under control. Learn more about Clear Inflammatory Response.