Hypoxia and Innate Immunity: Keeping Up with the HIFsters

Abstract

Recent years have witnessed an emergence of interest in understanding metabolic changes associated with immune responses, termed immunometabolism. As oxygen is central to all aerobic metabolism, hypoxia is now recognized to contribute fundamentally to inflammatory and immune responses. Studies from a number of groups have implicated a prominent role for oxygen metabolism and hypoxia in innate immunity of healthy tissue (physiologic hypoxia) and during active inflammation (inflammatory hypoxia). This inflammatory hypoxia emanates from a combination of recruited inflammatory cells (e.g., neutrophils, eosinophils, and monocytes), high rates of oxidative metabolism, and the activation of multiple oxygen-consuming enzymes during inflammation. These localized shifts toward hypoxia have identified a prominent role for the transcription factor hypoxia-inducible factor (HIF) in the regulation of innate immunity. Such studies have provided new and enlightening insight into our basic understanding of immune mechanisms, and extensions of these findings have identified potential therapeutic targets. In this review, we summarize recent literature around the topic of innate immunity and mucosal hypoxia with a focus on transcriptional responses mediated by HIF.

Keywords: dendritic cell; epithelia; granulocyte; immunometabolism; inflammation; macrophage; monocyte; prolyl hydroxylase.

Figure 1

The microbiome is a vital determinant of mucosal oxygen levels in the gastrointestinal tract. Pimonidazole staining (red), which detects areas of severe hypoxia (pO₂ < 10 mm Hg) in tissues, demonstrates a lack of physiologic hypoxia in the large intestine of germ-free mice lacking a microbiome (a) compared to conventional mice with an intact microbiome (b).

Figure 2

Mechanisms of HIF activation in the inflamed intestinal mucosa. HIF activation in the inflamed intestinal mucosa can occur as a result of at least five distinct mechanisms. (①) Decreased oxygen supply caused by vascular damage or ischemia leading to mucosal hypoxia. (②) Increased oxygen demand caused by high levels of oxygen consumption by transmigrating neutrophils and eosinophils leading to mucosal hypoxia. (③) Cytokine-mediated increases in HIF-1α transcription. (④) Extracellular purinergic signaling through PMNs and platelet-derived ATP and Ap3A. (⑤) Increased epithelial oxygen consumption or iron chelation induced by components of the microbiome. Abbreviation: PMN, polymorphonuclear leukocyte.

Figure 3

HIF mediates cell-type-specific influences on distinct populations of innate immune cells. When exposed to hypoxia, HIF becomes stabilized and activated in cells of the innate immune system. However, the cohorts of HIF-dependent target genes that are activated differ between cell types, which can lead to cell-specific consequences of HIF activation. Abbreviation: DC, dendritic cell.

Figure 4

Opposing mucosal oxygen gradients exist at distinct anatomical barriers. (a) In the gastrointestinal mucosa, a steep oxygen gradient exists from the well-oxygenated capillary bed to the anoxic lumen of the gut, rendering the epithelium in a state of physiologic hypoxia. (b) By contrast, in the alveolar compartment of the lung, a steep oxygen gradient exists from the highly oxygenated lumen of the airway to the subepithelial compartment, where oxygen is efficiently removed.

Figure 5

Therapeutic intervention in the HIF pathway. A range of pharmacologic agents with distinct mechanisms of action have been developed to either inhibit or activate the HIF pathway.