COVID-19 triggers macrophage-mediated cytokine storm in diabetic patients

Researchers from the University of Michigan have created a new therapeutic recipe that could help people with underlying health conditions like type 2 diabetes reduce their risk of developing chronic inflammation in response to COVID-19. Macrophages are key players in controlling excess inflammation due to the coronavirus 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 William J. Melvin, MD, from the Section of Vascular Surgery, Department of Surgery, theorized 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.”

Reference

Melvin WJ, Audu CO, Davis FM, et al. Coronavirus induces diabetic macrophage-mediated inflammation via SETDB2. Proc Natl Acad Sci 2021;118:e2101071118; https://doi.org/10.1073/pnas.2101071118