Innate immune signalling at the intestinal epithelium in homeostasis and disease

Abstract

The intestinal epithelium--which constitutes the interface between the enteric microbiota and host tissues--actively contributes to the maintenance of mucosal homeostasis and defends against pathogenic microbes. The recognition of conserved microbial products by cytosolic or transmembrane pattern recognition receptors in epithelial cells initiates signal transduction and influences effector cell function. However, the signalling pathways, effector molecules and regulatory mechanisms involved are not yet fully understood, and the functional outcome is poorly defined. This review analyses the complex and dynamic role of intestinal epithelial innate immune recognition and signalling, on the basis of results in intestinal epithelial cell-specific transgene or gene-deficient animals. This approach identifies specific epithelial cell functions within the diverse cellular composition of the mucosal tissue, in the presence of the complex and dynamic gut microbiota. These insights have thus provided a more comprehensive understanding of the role of the intestinal epithelium in innate immunity during homeostasis and disease.

Figure 1

Structural features of the intestinal mucosa. Paraffin-embedded, formalin-fixed sections of small intestinal (upper panel) and colon tissue (lower panel) from a C57Bl/6 mouse were stained as described elsewhere [49]. E-cadherin (E-cad) is shown in red and CD3 in green. The highly polarized epithelium of the small intestine is organized in a crypt–villus structure. Crypts provide a protective niche for proliferating stem cells (not depicted), and continuous migration along the crypt–villi axis is accompanied by IEC differentiation. The Paneth cells (small white vesicles) are next to the stem cells at the bottom of the crypts, and goblet cells (large white vesicles) are dispersed along the crypt and lower villus region. These two cell types generate the mucus barrier. T cells are shown as an example of intestinal immune cells; lymphocytes can be seen in between or adjacent to the epithelium (IELs) or within the lamina propria (LPL). Epithelium organization in the colon: the crypts end in a flat surface without villi, generating a smoother mucosal tissue. A large number of goblet cells produce a dense mucus layer that covers the epithelium (not depicted). There are no Paneth cells in the healthy colon and the number of immune cells in the lamina propria is much lower than in the small intestine. IEC, intestinal epithelial cell; IEL, intraepithelial lymphocytes; LPL, lamina propria lymphocytes, WGA, wheat germ agglutinin.

Figure 2

Intestinal epithelial cells in microbial homeostasis. The microbiota and microbiota-derived immune stimuli are shown in red. IECs, which are the communicators between microbiota and professional immune cells, and IEC-mediated effects are shown in yellow. Immune cells and their influence on epithelial barrier formation and IgA-mediated mucosal host protection are shown in blue. Please refer to the text for details. AMP, antimicrobial peptide; IEC, intestinal epithelial cell,; LPS, lipopolysaccharide; PSA, polysaccharide A; TGF-β, transforming growth factor beta; TNF, tumour necrosis factor; TSLP, thymic stromal lymophopoietin; MIP2, macrophage inflammatory protein 2.

Figure 3

Generation of IEC-specific gene-deficient animals. Transgenic mice carrying cre-recombinase (cre) under the control of the IEC-specific villin or I-Fabp promoter are cross-bred with mice that encode the target gene flanked by loxP sites. Expression of the cre-recombinase in IECs leads to excision of the region flanked by loxP sites in the target gene and thereby the generation of an IEC-specific gene-deficient mouse. IEC, intestinal epithelial cell; I-Fabp, intestinal fatty acid-binding protein.

Figure 4

Innate immune signalling in IECs. (A) Both pathogenic and commensal microorganisms stimulate innate immune receptors in IECs, such as TLRs, NLRs and RLRs. Gene expression is induced among other pathways through IKK1 and 2, NEMO and RelA/p65. Inflammasome activation leads to pro-IL-1β and pro-IL-18 cleavage by caspase 1, resulting in IL-1β and IL-18 secretion. The functional relevance of the inflammasome in IECs has not formally been shown. Innate immune signalling in IECs is also controlled by negative regulatory factors, such as SIGIRR/TIR8, A20 and PPARγ. IEC stimulation leads to the secretion of antimicrobial effectors, such as defensins and RegIIIγ, as well as the immunomodulatory Alpi, reinforces tight junctions and drives intraepithelial communication through the production of ROS and IL-17C. In addition, it facilitates cross-talk to professional immune cells of the lamina propria, leading to the recruitment of IELs through the secretion of IL-15 and IL-7, and stimulating CX₃CR1⁺ non-migratory phagocytes to sample the luminal content. Finally, epithelial cell differentiation, proliferation and survival is influenced by the secretion of a variety of soluble mediators, such as CCL20, CCL28, April, TSLP and TGF-β is stimulated. (B) When the intestinal epithelial barrier loses integrity, commensal bacteria can translocate to the subepithelial tissue, inducing the secretion of proinflammatory mediators and leukocyte recruitment. This, in turn, induces organ dysfunction, reduced nutrient and water absorption, and can lead to mucosal inflammation and clinical disease. If the situation becomes chronic, it can impair wound healing and contribute to the development of disorders such as inflammatory bowel disease.