HIF-1α Regulation of Cytokine Production following TLR3 Engagement in Murine Bone Marrow–Derived Macrophages Is Dependent on Viral Nucleic Acid Length and Glucose Availability

Abstract

Hypoxia-inducible factor-1α (HIF-1α) is an important regulator of glucose metabolism and inflammatory cytokine production in innate immune responses. Viruses modulate HIF-1α to support viral replication and the survival of infected cells, but it is unclear if this transcription factor also plays an important role in regulating antiviral immune responses. In this study, we found that short and long dsRNA differentially engage TLR3, inducing distinct levels of proinflammatory cytokine production (TNF-α and IL-6) in bone marrow–derived macrophages from C57BL/6 mice. These responses are associated with differential accumulation of HIF-1α, which augments NF-κB activation. Unlike TLR4 responses, increased HIF-1α following TLR3 engagement is not associated with significant alterations in glycolytic activity and was more pronounced in low glucose conditions. We also show that the mechanisms supporting HIF-1α stabilization may differ following stimulation with short versus long dsRNA and that pyruvate kinase M2 and mitochondrial reactive oxygen species play a central role in these processes. Collectively, this work suggests that HIF-1α may fine-tune proinflammatory cytokine production during early antiviral immune responses, particularly when there is limited glucose availability or under other conditions of stress. Our findings also suggest we may be able to regulate the magnitude of proinflammatory cytokine production during antiviral responses by targeting proteins or molecules that contribute to HIF-1α stabilization.

Hypoxia inducible factor-1α related mechanism and TCM intervention in process of early fracture healing

“…The occurrence of this coordination effect depends on the gene expression of HIF-1α, and its multiple downstream cytokines play an important role in angiogenesis, bone regeneration and bone remodeling ( Miclau et al, 2017 , Wilson, Wong, Toupadakis, & Yellowley, 2015 ). In recent years, studies have reported that HIF-1α contributes to the healing of osteoporotic fractures and the recovery of various bone diseases ( Ahmed et al, 2021 , Hirai et al, 2018 , Silagi, Schipani, Shapiro, & Risbud, 2021 , Tian et al, 2022 , Wang et al, 2021 , Wang et al, 2021 , Wang et al, 2021 , Zhang et al, 2022 , Zhao et al, 2021 ). At the same time, it can promote bone regeneration and protect bone cells ( Xu et al, 2021 , Zhao et al, 2021 ).…”