Hypoxia/HIF Modulates Immune Responses

Abstract

Oxygen availability varies throughout the human body in health and disease. Under physiological conditions, oxygen availability drops from the lungs over the blood stream towards the different tissues into the cells and the mitochondrial cavities leading to physiological low oxygen conditions or physiological hypoxia in all organs including primary lymphoid organs. Moreover, immune cells travel throughout the body searching for damaged cells and foreign antigens facing a variety of oxygen levels. Consequently, physiological hypoxia impacts immune cell function finally controlling innate and adaptive immune response mainly by transcriptional regulation via hypoxia-inducible factors (HIFs). Under pathophysiological conditions such as found in inflammation, injury, infection, ischemia and cancer, severe hypoxia can alter immune cells leading to dysfunctional immune response finally leading to tissue damage, cancer progression and autoimmunity. Here we summarize the effects of physiological and pathophysiological hypoxia on innate and adaptive immune activity, we provide an overview on the control of immune response by cellular hypoxia-induced pathways with focus on the role of HIFs and discuss the opportunity to target hypoxia-sensitive pathways for the treatment of cancer and autoimmunity.

Keywords: B cells; HIF; ILC; T cells; hypoxia; macrophages; monocytes; neutrophils; oxygen.

Figure 1

Oxygen partial pressure (pO₂) varies throughout the human body from main organs to lymphoid tissues. Figure was modified from Servier Medical Art, licensed under a Creative Common Attribution 3.0 Generic License [16].

Figure 2

Hypoxia arises in a variety of immunological situations under physiological and pathophysiological immune activity. Physiological hypoxia which is attributed to be moderate and constant is caused by, e.g., oxygen gradients as a result of developmental processes, anatomic structure and functional composition. The factors contributing to physiological hypoxia differ in specific organs such as in primary and secondary lymphoid organs. Here, physiological hypoxia regulates the function of immune cells supporting beneficial immune activity (light red right panel). The pathophysiological hypoxia is usually attributed to be severe and confused, which is caused by a variety of factors in different diseases (dark red left panel). (↑: induced or up-regulated, ↓: reduced or down-regulated. PMN, polymorphonuclear neutrophils; EPO, erythropoietin; HSC, hematopoietic stem cell).

Figure 3

(A) Structure of hypoxia-inducible factor (HIF)-1α/HIF-2α subunit. Basic helix-loop-helix (bHLH) domain of HIF-α mediates DNA binding, and PAS domain is required for heterodimerization of the subunits. N-terminal transactivation domain (N-TAD) and the C-terminal transactivation domain (C-TAD) are transactivation domains for activation of HIF target genes. The N-TAD is responsible for the stability and target gene specificity and overlaps with the oxygen-dependent degradation domain (ODDD). The C-TAD interacts with coactivators activating gene transcription. Protein von Hippel–Lindau (pVHL)-mediated degradation of HIF-α needs hydroxylation of two proline residues in (ODDD). (B) Cellular HIF-α regulation under hypoxic (red shaded area of triangle) and normoxia conditions (blue shaded area of triangle). In hypoxia, HIF-α subunit translocates into nucleus and dimerizes with constitutively expressed HIF-β subunit, then recruits the transcriptional coactivator p300 and CREB (cAMP response element binding)-binding protein (CBP) to form a complex, which binds to hypoxic response elements (HRE) on DNA and triggers HIF-dependent transcriptional response. Under normoxic condition, when cellular oxygen supply exceeds demand, HIF-α is hydroxylated on prolyl residues by prolyl hydroxylase domain proteins (PHDs), which are members of 2-oxoglutarate (2-OG)-dependent dioxygenase superfamily and function in the present of substrates and co-factors: oxygen (O2), 2-oxoglutarate (2-OG), ferrous iron [Fe (II)] and ascorbate. Hydroxylation facilitates the interaction with the tumor suppressor protein von Hippel–Lindau (pVHL), which recruits an E3-ubiquiine-ligase complex tagging HIF by polyubiquitination for proteasomal degradation via the 26S proteasome. Furthermore, factor-inhibiting HIF (FIH) hydroxylates HIF and inhibits the transcriptional activation of HIF by preventing recruitment of the transcriptional coactivators p300 and CBP. Figure was modified from Servier Medical Art, licensed under a Creative Common Attribution 3.0 Generic License [16].

Figure 4

Impact of hypoxia on mitochondrial functions. Under normoxia, pyruvate is shifted into the mitochondria and catalyzed to Acetyl coenzyme A (Acetyl-CoA) as a substrate for the TCA cycle (tricarboxylic acid cycle) to synthesize energy-rich reductants (NADH and FADH₂) which drive the electron flux through the ETC and provide Aspartate. Under hypoxia, pyruvate is catalyzed to lactate while only few amounts of Acetyl-CoA are provided by fatty acid oxidation to the TCA. Only low amounts of energy-rich reductants and ATP are produced. The lack of the final electron acceptor (oxygen) leads to ROS generation during electron flux through the ETC. (Large arrows indicate higher flux; smaller arrows indicate lower flux; larger icons indicate higher amounts of intermediates; smaller icons indicate lower amounts of intermediates). Figure was modified from Servier Medical Art, licensed under a Creative Common Attribution 3.0 Generic License [16].

Figure 5

Extracellular regulation of HIF-α. A schematic summarizing the mechanisms underlying the regulation of HIFα activity under diverse physiological and pathological conditions. Arrow indicates activation, and bar-headed line indicates inhibition.