Coronavirus induces diabetic macrophage-mediated inflammation via SETDB2

COVID-19 induces a robust, extended inflammatory cytokine storm that contributes to an increased morbidity and mortality, particularly in patients with type 2 diabetes (T2D). Macrophages are a key innate immune cell population responsible for the cytokine storm that has been shown, in T2D, to promote excess inflammation in response to infection. Using peripheral monocytes and sera from human patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and a murine hepatitis coronavirus (MHV-A59) (an established murine model of SARS), we identified that coronavirus induces an increased M phi-mediated inflammatory response due to a coronavirus-induced decrease in the histone methyltransferase, SETDB2. This decrease in SETDB2 upon coronavirus infection results in a decrease of the repressive trimethylation of histone 3 lysine 9 (H3K9me3) at NFkB binding sites on inflammatory gene promoters, effectively increasing inflammation. M phi s isolated from mice with a myeloid-specific deletion of SETDB2 displayed increased pathologic inflammation following coronavirus infection. Further, IFN beta directly regulates SETDB2 in M phi s via JaK1/STAT3 signaling, as blockade of this pathway altered SETDB2 and the inflammatory response to coronavirus infection. Importantly, we also found that loss of SETDB2 mediates an increased inflammatory response in diabetic M phi s in response to coronavirus infection. Treatment of coronavirus-infected diabetic M phi s with IFN beta reversed the inflammatory cytokine production via up-regulation of SETDB2/H3K9me3 on inflammatory gene promoters. Together, these results describe a potential mechanism for the increased M phi-mediated cytokine storm in patients with T2D in response to COVID-19 and suggest that therapeutic targeting of the IFN beta/SETDB2 axis in T2D patients may decrease pathologic inflammation associated with COVID-19.

Automated summary

COVID-19 induces a strong inflammatory response, particularly in patients with type 2 diabetes. Research has shown that coronavirus infection decreases the level of histone methyltransferase, contributing to increased inflammation.