HIF1α-dependent glycolysis promotes macrophage functional activities in protecting against bacterial and fungal infection

Abstract

Macrophages are important innate immune defense system cells in the fight against bacterial and fungal pathogenic infections. They exhibit significant plasticity, particularly with their ability to undergo functional differentiation. Additionally, HIF1α is critically involved in the functional differentiation of macrophages during inflammation. However, the role of macrophage HIF1α in protecting against different pathogenic infections remains unclear. In this study, we investigated and compared the roles of HIF1α in different macrophage functional effects of bacterial and fungal infections in vitro and in vivo. We found that bacterial and fungal infections produced similar effects on macrophage functional differentiation. HIF1α deficiency inhibited pro-inflammatory macrophage functional activities when cells were stimulated with LPS or curdlan in vitro or when mice were infected with L. monocytogenes or C. albicans in vivo, thus decreasing pro-inflammatory TNFα and IL-6 secretion associated with pathogenic microorganism survival. Alteration of glycolytic pathway activation was required for the functional differentiation of pro-inflammatory macrophages in protecting against bacterial and fungal infections. Thus, the HIF1α-dependent glycolytic pathway is essential for pro-inflammatory macrophage functional differentiation in protecting against bacterial and fungal infections.

Iron accumulation in microglia triggers a cascade of events that leads to altered metabolism and compromised function in APP/PS1 mice

“…It has been suggested that, in macrophages, the increase in glycolysis is necessary to facilitate the maintenance of the inflammatory response and that this, at least in some circumstances, is primarily dependent on increased glucose uptake, increased hexokinase activity and increased PFKFB3 triggered by HIF‐1α . Indeed, recent findings revealed that the LPS‐induced inflammatory and metabolic response in macrophages is dependent on HIF‐1α and also demonstrated that inflammatory and metabolic response induced in macrophages by infection of mice with L. monocytogenes or C. albicans was compromised in HIF‐1α −/− mice . Here we show that IFNγ+Aβ increases both HIF‐1α and reactive oxygen species production providing indirect evidence that these factors play a role in modulating PFKFB3 in microglia as they do in other cells.…”

Transcriptomic Profiles of Monocyte-Derived Macrophages in Response to Escherichia coli is Associated with the Host Genetics

“…The expression of HIF1A after stimulation of macrophage with LPS has been previously documented. The role of HIF1A in regulation of metabolic process and pro-inflammatory characteristics of macrophages is also known 42,43 . However, the results of the current study suggest a genetic regulation mechanism on activation of HIF1A.…”

Von Hippel-Lindau Protein Is Required for Optimal Alveolar Macrophage Terminal Differentiation, Self-Renewal, and Function

“…We hypothesized that sensing the increased oxygen concentration just after birth may be important for postnatal AM maturation. Hypoxia-inducible transcription factors (HIFs) are the master regulators of the transcriptional response to low oxygen tensions, and HIF depletion affects macrophage physiology ( Imtiyaz et al., 2010 , Li et al., 2018 , Peyssonnaux et al., 2005 ). Under normoxia, HIF-α subunits are hydroxylated and bind to the Von Hippel-Lindau tumor suppressor protein (VHL), which is part of an E3 ubiquitin ligase complex targeting HIF-α subunits for proteasomal degradation.…”