LAUSR

Significance Clinical studies have shown that defects in type I interferon (IFN) production or antibodies to IFN appear to correlate with severe COVID-19 infection. Here, we demonstrate that proinflammatory cytokines but not type I IFN are produced by hypoxic human monocytes. We show that hypoxia suppresses production of type I IFN but not nuclear factor-κB–dependent proinflammatory cytokines. We demonstrate that hypoxia-inducible factor-1α is a direct transcriptional suppressor of interferon regulatory factors, the transcriptional activators of type I IFN. These findings may aid in understanding and control of impaired IFN production by severe acute respiratory syndrome coronavirus 2 infection. Patients with severe COVID-19 infection exhibit a low level of oxygen in affected tissue and blood. To understand the pathophysiology of COVID-19 infection, it is therefore necessary to understand cell function during hypoxia. We investigated aspects of human monocyte activation under hypoxic conditions. HMGB1 is an alarmin released by stressed cells. Under normoxic conditions, HMGB1 activates interferon regulatory factor (IRF)5 and nuclear factor-κB in monocytes, leading to expression of type I interferon (IFN) and inflammatory cytokines including tumor necrosis factor α, and interleukin 1β, respectively. When hypoxic monocytes are activated by HMGB1, they produce proinflammatory cytokines but fail to produce type I IFN. Hypoxia-inducible factor-1α, induced by hypoxia, functions as a direct transcriptional repressor of IRF5 and IRF3. As hypoxia is a stressor that induces secretion of HMGB1 by epithelial cells, hypoxia establishes a microenvironment that favors monocyte production of inflammatory cytokines but not IFN. These findings have implications for the pathogenesis of COVID-19.