Elsevier

Molecular Aspects of Medicine

Volumes 47–48, February–March 2016, Pages 24-34
Molecular Aspects of Medicine

Review
The role of HIF in immunity and inflammation

https://doi.org/10.1016/j.mam.2015.12.004Get rights and content

Abstract

Uncontrolled or non-resolving inflammation underpins a range of disease states including rheumatoid arthritis, inflammatory bowel disease and atherosclerosis. Hypoxia is a prominent feature of chronically inflamed tissues. This is due to elevated oxygen consumption by highly metabolically active inflamed resident cells and activated infiltrating immunocytes, as well as diminished oxygen supply due to vascular dysfunction. Tissue hypoxia can have a significant impact upon inflammatory signaling pathways in immune and non-immune cells and this can impact upon disease progression. In this review, we will discuss the relationship between tissue hypoxia and inflammation and identify how hypoxia-sensitive signaling pathways are potential therapeutic targets in chronic inflammatory disease.

Section snippets

Hypoxia in inflammation

Metazoans have evolved a highly efficient bio-energetic strategy, which involves the oxidative metabolism of carbohydrates and fatty acids to produce biochemical energy equivalents in the form of adenosine triphosphate (ATP). This process occurs in mitochondria in the presence of sufficient levels of molecular oxygen (O2). Under normal circumstances, the majority of oxygen available in a tissue is consumed during oxidative metabolism; however, a reserve of non-mitochondrial oxygen is also

The hypoxia-inducible factor (HIF)

Because a continuous supply of molecular oxygen is essential for cell, tissue and organism survival, it is perhaps not surprising that metazoans have evolved multiple mechanisms by which to adapt to and survive periods of hypoxia (Kaelin and Ratcliffe, 2008). The primary signaling pathway activated by hypoxia involves the stabilization of the hypoxia-inducible factor (HIF) (Semenza, 2012). Because the HIF pathway has been extensively reviewed elsewhere in this series, it will be only briefly

Nuclear factor kappaB (NF-κB)

NF-κB is a master regulator of genes involved in innate immunity, inflammation and apoptosis. The NF-κB family is composed of five related proteins p65 (RelA, NFκB3), p50 (NFκB1), p52 (NFκB2), c-Rel and RelB (13). NF-κB is activated through a series of phosphorylation events usually initiated following activation of cell surface receptors that recognize specific inflammatory stimuli (e.g. toll-like receptors and cytokine receptors). Diverse stimuli such as interleukin 1β (IL-1β),

NF-κB and HIF cross-talk

NF-κB and HIF signaling are interdependent. NF-κB has been shown to play a role in basal and stimulated HIF-1α mRNA expression. The, p50 and p65 NF-κB subunits can bind to a κB binding site located in the HIF-1α promoter in response to hypoxia. When these subunits are overexpressed, an increase in HIF-1α mRNA levels and promoter activity is observed. Subsequent mutation of this κB site in the HIF-1α promoter prevented hypoxic induction of HIF-1α promoter activity. Furthermore, a dominant

Regulation of immune effector pathways by HIF

In this section, we will focus on the function(s) of the HIF and the HIF-hydroxylases in specific immune cell sub-types of both the innate and adaptive immune systems. This has been an area of intense research over the last decade with the use of genetically modified organisms in multiple models of infection/inflammation being investigated. We will attempt to reconcile the data emerging from the different experimental approaches to give an overview of the importance of the HIF pathway and

Myeloid cells

HIF-1α and HIF-2α levels are increased in primary human macrophages exposed to hypoxia (Burke et al., 2002). Indications as to the importance of a functional oxygen-sensing pathway in immune cells were first provided by Cramer et al. (2003). Using a targeted deletion of HIF-1α in the myeloid cell lineage (granulocytes and monocytes/macrophages) achieved by cre expression driven by the lysozyme M promoter, they observed a profound effect of HIF-1α loss on myeloid cell metabolism. It is known

Lymphocytes

T-lymphocytes (T-cells) are key immune cell-types of the adaptive immune response. Lymphoid progenitors originating in the bone marrow migrate to the thymus for maturation and they can differentiate into a variety of subtypes including T helper (Th) (CD4+), cytotoxic T-cell (CD8+) and T regulatory (T-Reg) cells (Femke Broere et al., 2011). These cells can then reside in primary or secondary lymphoid tissue. This migratory and differentiation life-cycle ensures that these lymphocytes encounter

Myeloid cells

The genetic approaches detailed above have been very informative in defining the role of the HIFα subunits in the myeloid cell response to low oxygen. The contribution of specific prolyl and asparagynl hydroxylases to these cellular effects has been further investigated using whole animal or conditional knock out of PHDs1–3.

PHD-2 is the hydroxylase that is most associated with the oxygen-dependent degradation of HIFα (Berra et al., 2003). Whole animal PHD2 deletion is embryonic lethal (Takeda

Lymphocytes

As discussed above, the role of HIF in the context of tumor biology is complex. Mamlouk et al. investigated the role of PHD2 in conditional knockout mouse under the control of CD68-cre. This mouse lacked PHD2 in a number of cell types (Franke et al., 2013), which was associated with a suppression of tumor growth. Using further genetic tools Mamlouk et al. were able to implicate loss of PHD2 in myeloid cells and T-lymphocytes together as key cells involved in conferring the tumor suppression

Pharmacological PHD inhibition

The discussion above of the complex roles of oxygen-sensing hydroxylases and the HIF pathway in inflammation give rise to the question: what is the net effect of hypoxia/hydroxylase inhibition and the activation of the HIF pathway on inflammation? This is probably the most pertinent question from the point of view of potential therapeutic interventions in inflammatory disease. Because HIF performs many pro- and anti-inflammatory functions in different immune and non-immune cell sub-types, it

References (80)

  • D.A. Hallback

    Evidence for the existence of a countercurrent exchanger in the small intestine in man

    Gastroenterology

    (1978)
  • W.G. Kaelin et al.

    Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway

    Mol. Cell

    (2008)
  • A. Mancino

    Divergent effects of hypoxia on dendritic cell functions

    Blood

    (2008)
  • A. Palazon

    HIF transcription factors, inflammation, and immunity

    Immunity

    (2014)
  • G.L. Semenza

    Hypoxia-inducible factors in physiology and medicine

    Cell

    (2012)
  • K.L. Talks

    The expression and distribution of the hypoxia-inducible factors HIF-1alpha and HIF-2alpha in normal human tissues, cancers, and tumor-associated macrophages

    Am. J. Pathol

    (2000)
  • M.M. Tambuwala

    Loss of prolyl hydroxylase-1 protects against colitis through reduced epithelial cell apoptosis and increased barrier function

    Gastroenterology

    (2010)
  • M.M. Tambuwala

    Targeted delivery of the hydroxylase inhibitor DMOG provides enhanced efficacy with reduced systemic exposure in a murine model of colitis

    J. Control. Release

    (2015)
  • A.A. Thompson

    Hypoxia-inducible factor 2α regulates key neutrophil functions in humans, mice, and zebrafish

    Blood

    (2014)
  • E. Berra

    HIF prolyl-hydroxylase 2 is the key oxygen sensor setting low steady-state levels of HIF-1alpha in normoxia

    EMBO J.

    (2003)
  • M.P. Biju et al.

    Vhlh gene deletion induces Hif-1-mediated cell death in thymocytes

    Mol. Cell. Biol

    (2004)
  • S. Bonello

    Reactive oxygen species activate the HIF-1alpha promoter via a functional NFkappaB site

    Arterioscler. Thromb. Vasc. Biol

    (2007)
  • B. Burke

    Expression of HIF-1alpha by human macrophages: implications for the use of macrophages in hypoxia-regulated cancer gene therapy

    J. Pathol

    (2002)
  • C.C. Caldwell

    Differential effects of physiologically relevant hypoxic conditions on T lymphocyte development and effector functions

    J. Immunol

    (2001)
  • E.L. Campbell et al.

    Neutrophils and inflammatory metabolism in antimicrobial functions of the mucosa

    J. Leukoc. Biol

    (2015)
  • N.S. Chandel

    Role of oxidants in NF-kappa B activation and TNF-alpha gene transcription induced by hypoxia and endotoxin

    J. Immunol

    (2000)
  • E.T. Clambey et al.

    Hypoxia-inducible factor-1 alpha-dependent induction of FoxP3 drives regulatory T-cell abundance and function during inflammatory hypoxia of the mucosa

    Proc. Natl. Acad. Sci. U.S.A.

    (2012)
  • M.E. Cockman

    Posttranslational hydroxylation of ankyrin repeats in IkappaB proteins by the hypoxia-inducible factor (HIF) asparaginyl hydroxylase, factor inhibiting HIF (FIH)

    Proc. Natl. Acad. Sci. U.S.A.

    (2006)
  • S.P. Colgan et al.

    Hypoxia: an alarm signal during intestinal inflammation

    Nat. Rev. Gastroenterol. Hepatol

    (2010)
  • E.P. Cummins et al.

    Hypoxia-responsive transcription factors

    Pflugers Arch

    (2005)
  • E.P. Cummins

    Prolyl hydroxylase-1 negatively regulates IkappaB kinase-beta, giving insight into hypoxia-induced NFkappaB activity

    Proc. Natl. Acad. Sci. U.S.A.

    (2006)
  • A.L. Doedens

    Macrophage expression of hypoxia-inducible factor-1 alpha suppresses T-cell function and promotes tumor progression

    Cancer Res

    (2010)
  • A.R. Elia et al.

    Human dendritic cells differentiated in hypoxia down-modulate antigen uptake and change their chemokine expression profile

    J. Leukoc. Biol

    (2008)
  • H.K. Eltzschig et al.

    Hypoxia and inflammation

    N. Engl. J. Med

    (2011)
  • H.K. Eltzschig et al.

    Targeting hypoxia signalling for the treatment of ischaemic and inflammatory diseases

    Nat. Rev. Drug Discov

    (2014)
  • S.G.A. Femke Broere et al.

    T cell subsets and T cell-mediated immunity

  • D.K. Finlay et al.

    PDK1 regulation of mTOR and hypoxia-inducible factor 1 integrate metabolism and migration of CD8+ T cells

    J. Exp. Med

    (2012)
  • K. Fluck et al.

    Oxygen sensing in intestinal mucosal inflammation

    Pflugers Arch

    (2016)
  • S. Frede

    Bacterial lipopolysaccharide induces HIF-1 activation in human monocytes via p44/42 MAPK and NF-kappaB

    Biochem. J.

    (2006)
  • S. Ghosh et al.

    New regulators of NF-kappaB in inflammation

    Nat. Rev. Immunol

    (2008)
  • Cited by (123)

    • Naringenin protects against septic cardiomyopathy in mice by targeting HIF-1α

      2024, Biochemical and Biophysical Research Communications
    • Role of HIF in fish inflammation

      2023, Fish and Shellfish Immunology
    View all citing articles on Scopus
    View full text