Regulation of immunity and inflammation by hypoxia in immunological niches

Abstract

Immunological niches are focal sites of immune activity that can have varying microenvironmental features. Hypoxia is a feature of physiological and pathological immunological niches. The impact of hypoxia on immunity and inflammation can vary depending on the microenvironment and immune processes occurring in a given niche. In physiological immunological niches, such as the bone marrow, lymphoid tissue, placenta and intestinal mucosa, physiological hypoxia controls innate and adaptive immunity by modulating immune cell proliferation, development and effector function, largely via transcriptional changes driven by hypoxia-inducible factor (HIF). By contrast, in pathological immunological niches, such as tumours and chronically inflamed, infected or ischaemic tissues, pathological hypoxia can drive tissue dysfunction and disease development through immune cell dysregulation. Here, we differentiate between the effects of physiological and pathological hypoxia on immune cells and the consequences for immunity and inflammation in different immunological niches. Furthermore, we discuss the possibility of targeting hypoxia-sensitive pathways in immune cells for the treatment of inflammatory disease.

Figure 1. Hypoxia in physiological immunological niches

The microenvironment of several physiological immunological niches is characterized by consistent and sustained oxygen gradients that lead to areas of stable physiological hypoxia. Depending on the tissue, the determinants of physiological oxygen gradients are varied. In these niches, physiological hypoxia regulates immune homeostasis through the control of resident immune cells. EPO, erythropoietin; HSC, haematopoietic stem cell.

Figure 2. Hypoxia in pathological immunological niches

The microenvironment of pathological immunological niches is frequently characterized by chaotic and severe oxygen gradients that lead to areas of pathological hypoxia. Depending on the tissue, the determinants of pathological hypoxia are varied. In these niches, pathological hypoxia can drive immune cell dysfunction, which contributes to disease progression. This dysfunction may lead to the promotion of tumour growth, ischaemia, inflammation and a worse outcome in infection. PMN, polymorphonuclear neutrophil.

Figure 3. The HIF pathway

Under conditions of normoxia, the majority of cellular oxygen consumption occurs in the mitochondria during the generation of ATP through oxidative phosphorylation, although some spare non-mitochondrial oxygen is available. Non-mitochondrial oxygen is utilized by hypoxia-inducible factor (HIF) hydroxylase enzymes to hydroxylate HIFα, resulting in its repression through targeted ubiquitylation by the E3 ubiquitin ligase von Hipple–Lindau disease tumour suppressor (pVHL), which results in proteasomal degradation and transcriptional repression by factor inhibiting HIF (FIH) (left side). In hypoxia, the absence of non-mitochondrial oxygen results in hydroxylase inhibition, the derepression of HIF and the activation of an adaptive transcriptional response (right side). CBP, CREB-binding protein; HRE, hypoxia response element; p300, histone acetyltransferase p300; PHD, prolyl hydroxylation domain; p_O2, partial pressure of oxygen; Ub, ubiquitin.