HIF-1α as a central mediator of cellular resistance to intracellular pathogens

Abstract

Hypoxia-inducible transcription factor-1α (HIF-1α) was originally identified as a master regulator of cellular responses to hypoxia. More recently, HIF-1α has emerged as a critical regulator of immune cell function that couples shifts in cellular metabolism to cell type-specific transcriptional outputs. Activation of macrophages with inflammatory stimuli leads to induction of the metabolic program aerobic glycolysis and to HIF-1α stabilization, which reinforce one another in a positive feedback loop that helps drive macrophage activation. This activation of aerobic glycolysis and HIF-1α is important both for production of inflammatory cytokines, such as IL-1β, and for cell intrinsic control of infection. Here, we review the importance of HIF-1α for control of bacterial, fungal, and protozoan intracellular pathogens, highlighting recent findings that reveal mechanisms by which HIF-1α is activated during infection and how HIF-1α coordinates antimicrobial responses of macrophages.

Figure 1.

In an O₂-dependent manner, prolyl hydroxylases (PHDs) hydroxylate HIF-1α, leading to ubiquitination by the Von Hippel-Lindau tumor suppressor protein (VHL) and targeting of the protein for degradation by the proteasome. HIF-1α protein stabilization can occur as a result of low O₂ conditions inhibiting hydroxylation by PHDs. In addition, PHDs can be inhibited by ROS, NO, and metabolites including succinate and fumarate.

Figure 2.

HIF-1α contributes to cell intrinsic control of epithelial cells infected with invasive UPEC or Chlamydia by inducing expression of iNOS and antimicrobial peptides. In macrophages, HIF-1α, aerobic glycolysis, and NO can promote each other through positive feedback mechanisms that provide host protection to intracellular bacterial pathogens. In the context of infection with the fungal pathogen Histoplasma capsulatum stabilization of HIF-1α results in inhibition of anti-inflammatory cytokine IL-10, while upregulating production of inflammatory cytokines and chemokines like IL-1β and CXCL1 which can promote neutrophil migration to sites of infection.