People with type 2 diabetes are at increased risk of severe COVID-19. More than 10% of US residents have diabetes, according to the International Diabetes Federation. In Russia, this figure is 6%.
Scientists at the University of Michigan in the United States have discovered that the severe course of coronavirus infection in patients with diabetes lacks the SETDB2 enzyme.
SETDB2 Enzyme Helps Heal Diabetic Ulcers
In the process of tissue repair, immune cells – macrophages – are involved. The most crucial property of macrophages is their plasticity – the ability to change their program depending on the stimulus.
Tissue damage leads to the accumulation of macrophages. To protect the body from bacteria and viruses, macrophages acquire pro-inflammatory and bactericidal properties. However, for tissue repair, macrophages change their properties to anti-inflammatory.
With a lack of SETDB2, macrophages lose their plasticity and retain their pro-inflammatory properties, disrupting the wound healing process. Usually, increased SETDB2 expression inhibits inflammation, and macrophages switch to a reparative program. However, in diabetes, macrophages express significantly less SETDB2, and program switching does not occur, which causes prolonged inflammation of diabetic ulcers.
Lack of SETDB2 Enzyme is The Cause of Severe COVID-19
Patients with type 2 diabetes often develop severe COVID-19 and a cytokine storm. One of the hallmarks of severe COVID-19 is producing large amounts of inflammatory signaling molecules called cytokines. In response to signaling molecules, immune cells release more cytokines. This vicious circle leads to a cytokine storm and tissue destruction. Poor coronavirus outcomes are usually attributed to the development of a cytokine storm, and elevated serum levels of cytokines TNFa, IL-6, and IL-8 predict severe COVID-19 and death. Primarily, the inflammatory cytokine storm in COVID-19 is caused by macrophages.
Scientists at the University of Michigan investigated pro-inflammatory human and mouse macrophages in the context of SARS-CoV-2 infection and murine hepatitis coronavirus MHV-A59. Research results:
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After infection with coronavirus, the level of the SETDB2 enzyme decreases in normal and diabetic macrophages. At the same time, the initial levels of SETDB2 in diabetic patients are lower; therefore, the decrease in the level of SETDB2 in diabetic macrophages is more significant.
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Due to a decrease in the level of SETDB2 during coronavirus infection in macrophages, the production of inflammatory cytokines IL-1β, TNFα, and IL-6 increases. And that increases the inflammation.
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The expression of SETDB2 in macrophages is regulated by interferon-beta (IFN-β) through the JaK1 / STAT3 signaling pathway.
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IFN-β levels are reduced in plasma of patients with COVID-19 and type 2 diabetes compared to patients with COVID-19 without diabetes. The same is observed in diabetic mice.
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A decreased type I interferon response is associated with COVID-19. The introduction of IFN-β into macrophages infected with coronavirus increases the expression of SETDB2 in diabetes and decreases the expression of inflammatory cytokines.
Conclusions
The SARS-CoV-2 coronavirus causes a decrease in SETDB2 levels. It leads to the uncontrolled production of inflammatory cytokines. In type 2 diabetes, SETDB2 decreases the most, which can lead to a cytokine storm.
In the plasma of patients with COVID-19 and type 2 diabetes, levels of interferon-beta are reduced. The administration of low doses of IFN-β reduces inflammation by increasing the level of SETDB2.
Interferon-beta administration is an important therapeutic strategy for COVID-19 with concomitant diabetes. With early interferon treatment, this strategy will help prevent cytokine storms.
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Source
Coronavirus induces diabetic macrophage-mediated inflammation via SETDB2
