Macrophage-mediated cytokine storm associated with COVID-19 infection in diabetic patients

A team of investigators from the University of Michigan may have unlocked a potential new recipe for counteracting the impact that COVID-19 has on patients with underlying disease processes such as type 2 diabetes.

Researchers at the University of Michigan, Ann Arbor, described a new potential recipe for counteracting the extremely deleterious effects that COVID-19 has on patients with underlying disease processes such as type 2 diabetes. Macrophages may be key to controlling that excess inflammation in response to infection.

This hyperinflammatory response, a so-called cytokine storm, in patients with severe COVID-19, results in increased morbidity and mortality in this patient population.

The researchers led by first author Dr William J. Melvin from the Section of Vascular Surgery, Department of Surgery, theorised that targeting the key players in the inflammatory response in patients with diabetes may result in less inflammation. They reported their results in Proceedings of the National Academy of Science.1

“Macrophages are a key innate immune cell population responsible for the cytokine storm that has been shown, in type 2 diabetes, to promote excess inflammation in response to infection,” the investigators commented.

They found that in both patients with type 2 diabetes infected with severe COVID-19 and an established murine model of SARS that the coronavirus induces an increased macrophage-mediated inflammatory response resulting from the viral-induced decrease in the enzyme SETDB2 in the macrophages. This in turn leads to increased transcription of inflammatory cytokines.

The investigators also found that interferon beta IFNβ regulates SETDB2 in the macrophages through the JaK1/STAT3 signaling pathway and that administration of IFNβ reverses the inflammation, particularly in the diabetic macrophages via increased levels of SETDB2.

These observations suggested to the research team “a potential mechanism for the increased macrophage-mediated cytokine storm in patients with type 2 diabetes in response to COVID-19 and suggests that therapeutic targeting of the IFNβ/SETDB2 axis … may decrease pathologic inflammation associated with COVID-19.”

Melvin WJ, Audu CO, Davis FM, et al. Coronavirus induces diabetic macrophage-mediated inflammation via SETDB2. Proc Natl Acad Sci 2021;118:e2101071118;