Hypoxia-inducible factor 1α is a negative regulator of IRF5 in hypoxic macrophages

Abstract Patients with severe Covid-19 exhibit a low level of oxygen in affected tissue and blood and a low interferon level in blood. It is necessary to understand cell function during hypoxia to understand the pathophysiology of Covid-19 infection. We investigated aspects of human monocyte activation under hypoxic conditions. HMGB1 is an alarmin released by stressed cells. Under normoxic conditions, HMGB1 activates IRF5 and NF-κB in monocytes, leading to type 1 interferon expression and the inflammatory cytokines TNFa and IL-1b, respectively. When hypoxic monocytes are activated by HMGB1, they produce pro-inflammatory cytokines but fail to produce type 1 interferon as HIF-1α functions as a direct transcriptional repressor of IRF5. Moreover, exposure to Dimethyloxaloylglycine (DMOG), which stabilizes HIF-1α, exhibits the same transcriptional program as hypoxia. These findings have implications for the pathogenesis of Covid-19 showing that a hypoxic microenvironment that favors macrophage production of inflammatory cytokines but not interferon.