Coronavirus induces diabetic macrophage-mediated inflammation via IFN-beta regulation of SETDB2

Abstract

Abstract COVID-19 induces a robust 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 sera from human patients with SARS-CoV-2 and a murine hepatitis coronavirus (MHV-A59) (an established murine model of SARS), we identified that coronavirus induces an increased Mϕ-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, increasing inflammation. Mϕs with a myeloid-specific deletion of SETDB2 displayed increased inflammation following coronavirus infection. Further, IFNβ directly regulates SETDB2 in Mϕs via JaK1/STAT3 signaling, as blockade of this pathway altered SETDB2 and the inflammatory response to coronavirus infection. Importantly, we also found that SETDB2 mediates a heightened inflammatory response in diabetic Mϕs in response to coronavirus infection. Treatment of coronavirus-infected diabetic Mϕs with IFNβ reversed the inflammatory cytokine production via upregulation of SETDB2/H3K9me3 on inflammatory gene promoters. Together, these results describe a potential mechanism for the increased Mϕ-mediated ‘cytokine storm’ in patients with T2D in response to COVID-19 and suggest that therapeutic targeting of the IFNβ/SETDB2 axis in T2D patients may decrease pathologic inflammation associated with COVID-19.