HIF-1alpha 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: 13.77). 08/2005; 115(7):1806-15. DOI: 10.1172/JCI23865
Source: PubMed

ABSTRACT 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
    [Show abstract] [Hide abstract]
    ABSTRACT: The release of extracellular traps (ETs) is a recently described mechanism of innate immune response to infection. Although ETs have been intensely investigated in the context of neutrophil antimicrobial effector mechanisms, other immune cells such as mast cells, eosinophils, and macrophages can also release these structures. The different ETs have several features in common, regardless of the type of cells from which they originated, including a DNA backbone with embedded antimicrobial peptides, proteases, and histones. However, they also exhibit remarkable individual differences such as the type of sub-cellular compartments from where the DNA backbone originates (e.g., nucleus or mitochondria), the proportion of responding cells within the pool, and/or the molecular mechanism/s underlying the ETs formation. This review summarizes the knowledge accumulated in recent years regarding the complex and expanding world of ETs and their role in immune function with particular emphasis on the role of other immune cells rather than on neutrophils exclusively.
    Frontiers in Immunology 01/2012; 3:420. DOI:10.3389/fimmu.2012.00420
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Erythropoietin (EPO) is a multi-functional cytokine, which exerts erythropoietic effects but also carries anti-apoptotic and immune-modulatory activities upon binding to two distinct receptors which are expressed on erythroid, parenchymal and immune cells, respectively. Whereas EPO ameliorates hemolytic anemia in malaria or trypanosomiasis and improves the course of autoimmune diseases such as inflammatory bowel disease or autoimmune encephalomyelitis, it deleteriously inhibits macrophage functions in Salmonella infection in animal models. Thus, the specific modulation of extra-erythropoietic EPO activity forms an attractive therapeutic target in infection and inflammation.
    Microbes and Infection 11/2011; 14(3):238-46. DOI:10.1016/j.micinf.2011.10.005 · 2.73 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: While it has long been suspected that inflammation participates in the pathogenesis of metabolic disorders such as the insulin resistance that occurs in type 2 diabetes, recent work suggests that this is not the only important interaction between metabolism and inflammation. Inroads into the understanding of the relationship between metabolic pathways and inflammation are indicating that signaling by innate immune receptors such as TLR4 and Nlrp3 regulate metabolism. TLRs have been shown to promote glycolysis, whilst Nlrp3-mediated production of IL-1β causes insulin resistance. A key role for the hypoxia-sensing transcription factor HIF1α in the functioning of macrophages activated by TLRs has also recently emerged. This review will assess recent evidence for these complex interactions and speculate on their importance for innate immunity and inflammation.
    FEBS letters 06/2011; 585(11):1568-72. DOI:10.1016/j.febslet.2011.05.008 · 3.34 Impact Factor