Mend Your Fences: The Epithelial Barrier and its Relationship With Mucosal Immunity in Inflammatory Bowel Disease

Abstract

The intestinal epithelium can be easily disrupted during gut inflammation as seen in inflammatory bowel disease (IBD), such as ulcerative colitis or Crohn's disease. For a long time, research into the pathophysiology of IBD has been focused on immune cell-mediated mechanisms. Recent evidence, however, suggests that the intestinal epithelium might play a major role in the development and perpetuation of IBD. It is now clear that IBD can be triggered by disturbances in epithelial barrier integrity via dysfunctions in intestinal epithelial cell-intrinsic molecular circuits that control the homeostasis, renewal, and repair of intestinal epithelial cells. The intestinal epithelium in the healthy individual represents a semi-permeable physical barrier shielding the interior of the body from invasions of pathogens on the one hand and allowing selective passage of nutrients on the other hand. However, the intestinal epithelium must be considered much more than a simple physical barrier. Instead, the epithelium is a highly dynamic tissue that responds to a plenitude of signals including the intestinal microbiota and signals from the immune system. This epithelial response to these signals regulates barrier function, the composition of the microbiota, and mucosal immune homeostasis within the lamina propria. The epithelium can thus be regarded as a translator between the microbiota and the immune system and aberrant signal transduction between the epithelium and adjacent immune cells might promote immune dysregulation in IBD. This review summarizes the important cellular and molecular barrier components of the intestinal epithelium and emphasizes the mechanisms leading to barrier dysfunction during intestinal inflammation.

Keywords: BMP, bone morphogenic protein; CD, Crohn's disease; Fz, frizzled; HD, humans α-defensin; IBD, inflammatory bowel disease; IECs, intestinal epithelial cells; IL, interleukin; Immune-Epithelial Crosstalk; Intestinal Epithelial Barrier; Intestinal Inflammation; JAMs, junctional adhesion molecules; Lgr5, leucine rich repeat containing G-protein coupled receptor 5; MARVEL, myelin and lymphocyte and related proteins for vesicle trafficking and membrane link; MLCK, myosin light chain kinase; NFκB, nuclear factor kappa-light-chain-enhancer of activated B cells; NOD-2, nucleotide-binding oligomerization domain-containing protein 2; STAT, signal transducer and activator of transcription; TAMP, tight junction–associated MARVEL protein; TJ, tight junction; TNF, tumor necrosis factor; TSLP, thymic stromal lymphopoietin; UC, ulcerative colitis.

Figure 1

Schematic depiction of the small intestinal crypt compartment and the 4 main driving signaling pathways for maintenance of the stem cell niche. All relevant intestinal cell types and signaling molecules are represented in the grey box. In summary, Paneth cells and mesenchymal cells are producers of Wnt ligands, which directly bind to frizzled receptors expressed by intestinal stem cells. Secretory precursors of the transit-amplifying compartment secrete Notch ligands, which bind to Notch receptors expressed by absorptive precursors. Hedgehog signals are produced by epithelial cells and act directly on Hedgehog receptor-expressing mesenchymal cells, preserving them to produce BMPs, which bind to their receptors expressed by epithelial cells counteracting the Wnt pathway. TA, transit-amplifying.

Figure 2

Paracellular intestinal barrier in health and inflammation. The paracellular barrier in healthy distal intestinal tissue is characterized by high expression levels of barrier-forming TJ proteins, which leads to a low paracellular permeability. In inflammation, the TJ barrier is disturbed. Channel-forming claudins are up-regulated in their expression (eg, by TNF-α or IL13), leading to an increased permeability for ions and water (pore pathway). Barrier-forming TJ proteins are down-regulated and can also be shifted into subjunctional regions or into endosomes, which further destabilizes the TJ barrier. Occludin, which is, besides tricellulin, involved in regulation of permeability for macromolecules, is also down-regulated by inflammatory processes (eg, by TNF-α or interferon-γ), leading to increased paracellular permeability for macromolecules (leak-pathway). IFN, interferon.

Figure 3

Representative model of mechanisms involved in mucosal healing. A few hours after epithelial injury (A), epithelial cells lose their polarity induced by the secretion of factors, such as TGF-α, TGF-β, or TFF (B). This induces epithelial cell migration to close the wound. After several hours, growth factors, cytokines, or bacterial/viral components induce the proliferation of IECs in the intestinal crypt (C). In a later phase, IECs differentiate into specialized IECs (D). For cell type nomenclature see Figure 1. TFF, Trefoil factor; TGF, transforming growth factor.