HIF-1α expression regulates the bactericidal capacity of phagocytes

Division of Biological Sciences, Department of Pediatrics, University of California, San Diego, La Jolla, CA, USA.
Journal of Clinical Investigation (Impact Factor: 13.22). 08/2005; 115(7):1806-15. DOI: 10.1172/JCI23865
Source: PubMed


Hypoxia is a characteristic feature of the tissue microenvironment during bacterial infection. Here we report on our use of conditional gene targeting to examine the contribution of hypoxia-inducible factor 1, alpha subunit (HIF-1alpha) to myeloid cell innate immune function. HIF-1alpha was induced by bacterial infection, even under normoxia, and regulated the production of key immune effector molecules, including granule proteases, antimicrobial peptides, nitric oxide, and TNF-alpha. Mice lacking HIF-1alpha in their myeloid cell lineage showed decreased bactericidal activity and failed to restrict systemic spread of infection from an initial tissue focus. Conversely, activation of the HIF-1alpha pathway through deletion of von Hippel-Lindau tumor-suppressor protein or pharmacologic inducers supported myeloid cell production of defense factors and improved bactericidal capacity. HIF-1alpha control of myeloid cell activity in infected tissues could represent a novel therapeutic target for enhancing host defense.

Download full-text


Available from: Thorsten Cramer, Feb 27, 2014
  • Source
    • "In fact, HIF1α−/− macrophages have impaired capacity to clear both Gram-positive and Gram-negative bacteria. Nevertheless, superoxide production during the respiratory burst, which is also required for bacterial clearance, seems to be a HIF1α-independent event (25). This is, interestingly, not the only HIF1α-independent event that occurs following classical activation. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Studying the metabolism of immune cells in recent years has emphasized the tight link existing between the metabolic state and the phenotype of these cells. Macrophages in particular are a good example of this phenomenon. Whether the macrophage obtains its energy through glycolysis or through oxidative metabolism can give rise to different phenotypes. Classically activated or M1 macrophages are key players of the first line of defense against bacterial infections and are known to obtain energy through glycolysis. Alternatively activated or M2 macrophages on the other hand are involved in tissue repair and wound healing and use oxidative metabolism to fuel their longer-term functions. Metabolic intermediates, however, are not just a source of energy but can be directly implicated in a particular macrophage phenotype. In M1 macrophages, the Krebs cycle intermediate succinate regulates HIF1α, which is responsible for driving the sustained production of the pro-inflammatory cytokine IL1β. In M2 macrophages, the sedoheptulose kinase carbohydrate kinase-like protein is critical for regulating the pentose phosphate pathway. The potential to target these events and impact on disease is an exciting prospect.
    Frontiers in Immunology 09/2014; 5:420. DOI:10.3389/fimmu.2014.00420
  • Source
    • "Hypoxia inducible factor-1 (HIF-1) is a transcription factor that is a major regulator of cellular adaption to low oxygen levels [1,2]. More recently, HIF has been recognized to play a role in host defense, promoting the bactericidal activity of phagocytic and epithelial cells and supporting innate immune activities of dendritic cells and mast cells [3-6]. HIF is comprised of a constitutively expressed β subunit that partners with dynamically regulated α subunits (HIF-1α, HIF-2α, or HIF-3α), which are unstable under normoxic conditions [7]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Hypoxia inducible factor-1 (HIF-1) is a major regulator of the cellular adaption to low oxygen stress and the innate immune function of myeloid cells. Treatment with the novel HIF-1 stabilizing drug AKB-4924 has been shown to enhance the bactericidal activity of keratinocytes as well as phagocytic cells. In this study, we sought to investigate the effect of pharmacological boosting of HIF-1 with AKB-4924 in keratinocytes and their contribution to the innate immune response. Treatment with the novel HIF-1 stabilizing drug AKB-4924 can increase keratinocyte production of pro-inflammatory cytokines in vitro and enhance neutrophil recruitment in vivo. HIF plays an important role in cytokine production by keratinocytes and in neutrophil recruitment to the skin. The HIF-boosting drug AKB-4924 has the potential to enhance the immune response even in the complex environment of bacterial skin infections.
    Journal of Inflammation 08/2013; 10(1):28. DOI:10.1186/1476-9255-10-28 · 2.02 Impact Factor
  • Source
    • "In addition to its role in promoting tumour growth, HIF-1α has also been implicated as modulator of immune responses. For example, the loss of HIF-1α impairs polymorphonuclear cell ability to kill bacteria (Peyssonnaux et al., 2005). In turn, cytokines such as interleukin-1 β, tumour necrosis factor α and interferon α can activate HIF-1α expression (Eltzschig and Carmeliet, 2011). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The role of oxygen tension level is a well-known phenomenon that has been studied in oncology and radiotherapy since about 60 years. Oxygen tension may inhibit or stimulate propagation of viruses in vitro as well as in vivo. In turn modulating oxygen metabolism may constitute a novel approach to treat viral infections as an adjuvant therapy. The major transcription factor which regulates oxygen tension level is hypoxia-inducible factor-1 alpha (HIF-1α). Down-regulating the expression of HIF-1α is a possible method in the treatment of chronic viral infection such as human immunodeficiency virus infection, chronic hepatitis B and C viral infections and Kaposi sarcoma in addition to classic chemotherapy. The aim of this review is to supply an updating concerning the influence of oxygen tension level in human viral infections and to evoke possible new therapeutic strategies regarding this environmental condition.
    Virology 07/2013; 444(1-2). DOI:10.1016/j.virol.2013.06.018 · 3.32 Impact Factor
Show more