ReviewThe role of HIF in immunity and inflammation
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)
Transmigrating neutrophils shape the mucosal microenvironment through localized oxygen depletion to influence resolution of inflammation
Immunity
(2014)PHD3 stabilizes the tight junction protein occludin and protects intestinal epithelial barrier function
J. Biol. Chem
(2015)Epidermal deletion of HIF-2α stimulates wound closure
J. Invest. Dermatol
(2014)HIF-1alpha is essential for myeloid cell-mediated inflammation
Cell
(2003)- et al.
Hydroxylases as therapeutic targets in inflammatory bowel disease
Lab. Invest
(2013) Control of TH 17/T reg balance by hypoxia-inducible factor 1
Cell
(2011)Oxygen levels in normal and previously irradiated human skin as assessed by EF5 binding
J. Invest. Dermatol
(2006)HIF-1α is a protective factor in conditional PHD2-deficient mice suffering from severe HIF-2α-induced excessive erythropoiesis
Blood
(2013)- et al.
Prolyl hydroxylase EGLN3 regulates skeletal myoblast differentiation through an NF-kappaB-dependent pathway
J. Biol. Chem
(2010) HIF-2alpha promotes hypoxic cell proliferation by enhancing c-myc transcriptional activity
Cancer Cell
(2007)
Evidence for the existence of a countercurrent exchanger in the small intestine in man
Gastroenterology
Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway
Mol. Cell
Divergent effects of hypoxia on dendritic cell functions
Blood
HIF transcription factors, inflammation, and immunity
Immunity
Hypoxia-inducible factors in physiology and medicine
Cell
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
Loss of prolyl hydroxylase-1 protects against colitis through reduced epithelial cell apoptosis and increased barrier function
Gastroenterology
Targeted delivery of the hydroxylase inhibitor DMOG provides enhanced efficacy with reduced systemic exposure in a murine model of colitis
J. Control. Release
Hypoxia-inducible factor 2α regulates key neutrophil functions in humans, mice, and zebrafish
Blood
HIF prolyl-hydroxylase 2 is the key oxygen sensor setting low steady-state levels of HIF-1alpha in normoxia
EMBO J.
Vhlh gene deletion induces Hif-1-mediated cell death in thymocytes
Mol. Cell. Biol
Reactive oxygen species activate the HIF-1alpha promoter via a functional NFkappaB site
Arterioscler. Thromb. Vasc. Biol
Expression of HIF-1alpha by human macrophages: implications for the use of macrophages in hypoxia-regulated cancer gene therapy
J. Pathol
Differential effects of physiologically relevant hypoxic conditions on T lymphocyte development and effector functions
J. Immunol
Neutrophils and inflammatory metabolism in antimicrobial functions of the mucosa
J. Leukoc. Biol
Role of oxidants in NF-kappa B activation and TNF-alpha gene transcription induced by hypoxia and endotoxin
J. Immunol
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.
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.
Hypoxia: an alarm signal during intestinal inflammation
Nat. Rev. Gastroenterol. Hepatol
Hypoxia-responsive transcription factors
Pflugers Arch
Prolyl hydroxylase-1 negatively regulates IkappaB kinase-beta, giving insight into hypoxia-induced NFkappaB activity
Proc. Natl. Acad. Sci. U.S.A.
Macrophage expression of hypoxia-inducible factor-1 alpha suppresses T-cell function and promotes tumor progression
Cancer Res
Human dendritic cells differentiated in hypoxia down-modulate antigen uptake and change their chemokine expression profile
J. Leukoc. Biol
Hypoxia and inflammation
N. Engl. J. Med
Targeting hypoxia signalling for the treatment of ischaemic and inflammatory diseases
Nat. Rev. Drug Discov
T cell subsets and T cell-mediated immunity
PDK1 regulation of mTOR and hypoxia-inducible factor 1 integrate metabolism and migration of CD8+ T cells
J. Exp. Med
Oxygen sensing in intestinal mucosal inflammation
Pflugers Arch
Bacterial lipopolysaccharide induces HIF-1 activation in human monocytes via p44/42 MAPK and NF-kappaB
Biochem. J.
New regulators of NF-kappaB in inflammation
Nat. Rev. Immunol
Cited by (123)
Naringenin protects against septic cardiomyopathy in mice by targeting HIF-1α
2024, Biochemical and Biophysical Research CommunicationsSerum hypoxia-inducible factor-1 alpha (HIF-1α) and apelin levels in children and adolescents diagnosed with autism spectrum disorder
2024, Research in Autism Spectrum DisordersRole of HIF in fish inflammation
2023, Fish and Shellfish ImmunologyCorrelation between hypoxia and HGF/c-MET expression in the management of pancreatic cancer
2023, Biochimica et Biophysica Acta - Reviews on Cancer