Hypoxia-dependent regulation of inflammatory pathways in immune cells

Abstract

Uncontrolled inflammation underpins a diverse range of diseases where effective therapy remains an unmet clinical need. Hypoxia is a prominent feature of the inflammatory microenvironment that regulates key transcription factors including HIF and NF-κB in both innate and adaptive immune cells. In turn, altered activity of the pathways controlled by these factors can affect the course of inflammation through the regulation of immune cell development and function. In this review, we will discuss these pathways and the oxygen sensors that confer hypoxic sensitivity in immune cells. Furthermore, we will describe how hypoxia-dependent pathways contribute to immunity and discuss their potential as therapeutic targets in inflammatory and infectious disease.

Figure 1. Regulation of immune cells by HIFs.

Functional immune cells differentiate from hematopoietic stem cells (HSC). Immune cells are frequently exposed to hypoxia when they enter the hypoxic niche of the inflammatory lesion where HIF can influence differentiation and function (shown in red).

Figure 2. Potential sites for functional hydroxylation in the NF-κB pathway.

NF-κB–dependent signaling can be activated by several proinflammatory factors that bind to discrete membrane-associated receptors and activate discrete pathways. Putative sites for functional hydroxylation in these pathways are outlined in red.

Figure 3. Mechanisms of therapeutic action of hydroxylase inhibitors in inflammation.

Pharmacological hydroxylase inhibition influences inflammatory processes by (1) enhancing barrier function (in infectious inflammation), (2) altering immune cell differentiation, and (3) altering innate and adaptive immune cell function.