Hypoxia Inducible Factor (HIF) Hydroxylases as Regulators of Intestinal Epithelial Barrier Function

Abstract

Human health is dependent on the ability of the body to extract nutrients, fluids, and oxygen from the external environment while at the same time maintaining a state of internal sterility. Therefore, the cell layers that cover the surface areas of the body such as the lung, skin, and gastrointestinal mucosa provide vital semipermeable barriers that allow the transport of essential nutrients, fluid, and waste products, while at the same time keeping the internal compartments free of microbial organisms. These epithelial surfaces are highly specialized and differ in their anatomic structure depending on their location to provide appropriate and effective site-specific barrier function. Given this important role, it is not surprising that significant disease often is associated with alterations in epithelial barrier function. Examples of such diseases include inflammatory bowel disease, chronic obstructive pulmonary disease, and atopic dermatitis. These chronic inflammatory disorders often are characterized by diminished tissue oxygen levels (hypoxia). Hypoxia triggers an adaptive transcriptional response governed by hypoxia-inducible factors (HIFs), which are repressed by a family of oxygen-sensing HIF hydroxylases. Here, we review recent evidence suggesting that pharmacologic hydroxylase inhibition may be of therapeutic benefit in inflammatory bowel disease through the promotion of intestinal epithelial barrier function through both HIF-dependent and HIF-independent mechanisms.

Keywords: CD, Crohn’s disease; DMOG, dimethyloxalylglycine; DSS, dextran sodium sulfate; Epithelial Barrier; FIH, factor inhibiting hypoxia-inducible factor; HIF, hypoxia-inducible factor; Hypoxia; Hypoxia-Inducible Factor (HIF) Hydroxylases; IBD, inflammatory bowel disease; IL, interleukin; Inflammatory Bowel Disease; NF-κB, nuclear factor-κB; PHD, hypoxia-inducible factor–prolyl hydroxylases; TFF, trefoil factor; TJ, tight junction; TLR, Toll-like receptor; TNF-α, tumor necrosis factor α; UC, ulcerative colitis; ZO, zonula occludens.

Figure 1

Representation of the intestinal epithelium in homeostatic conditions. In physiologic conditions, the intestinal epithelium forms a barrier that separates the anoxic and microorganism-rich lumen from the perfused and sterile lamina propria. Epithelial cells accomplish a variety of tasks: production of mucins, TFFs, and defensins; absorption of nutrients; sealing of the paracellular space; immune recognition; tolerance; and adaptation to oxygen tension changes. The external surface is covered by a layer of mucins that represent a nest for the intestinal microbiota. The inner surface is in contact with the resident immune system.

Figure 2

Alterations of barrier function are common in inflammatory bowel disease. The scheme represents the loss of barrier function mediated through increased apoptosis and induced TJ internalization. In pathologic situations, the intestinal epithelium becomes hypoxic as a result of the imbalance between oxygen supply and consumption. The intestinal epithelium also participates in the recruitment of immune cells through cytokine/chemokine release. Excessive activation of the immune system can in some cases lead to complications such as excessive extracellular matrix production, leading to tissue fibrosis.

Figure 3

Mechanisms of hydroxylase inhibition mediated intestinal anti-inflammatory effects. Described mechanisms include both HIF-dependent and -independent functions. HIF-dependent mechanisms include regulation of TFFs, defensins, and mucins. PHD-mediated actions include immune modulation and apoptosis regulation, implicating the NF-κB pathway.