Epithelial cells also express members of the intracellular NOD-like receptor (NLR) family, including gNLRP3, NLRC4, and NLRP6, that can form inflammasomes (see Fig. 12.15). As described in Section 3-9, formation of an inflammasome leads to activation of caspase 1, which cleaves pro-IL-1 and pro-IL-18 to produce the active cytokines (see Fig. 3.19). Both these cytokines contribute to epithelial defense against bacterial invasion by promoting barrier integrity, but can cause tissue damage if present for long periods.
One mechanism recently recognized as important for epithelial defense against infection is autophagy, which we discussed in Section 6-6 for its relationship to antigen processing. In this process, a crescent-shaped double-membrane fragment in the cytoplasm, called the isolation membrane, or phagophore, engulfs various cytoplasmic contents to form a complete vesicle, the autophagosome, which fuses with lysosomes to degrade the contents (see Fig. 12.15). When autophagy is disrupted, bacteria cannot be contained effectively, and epithelial cells become stressed. This can lead to increased penetration of bacteria into the body and to NFκB-mediated inflammation. Autophagy is promoted by the NOD1 and NOD2 intracellular bacterial sensors. As with NOD2, mutations in the autophagy-related genes ATG16L1 and IRGM1 are associated with susceptibility to Crohn’s disease in humans.
Certain specialized populations of epithelial cells have particularly important roles in innate immune defense of the intestine. Paneth cells are found only in the small intestine, where they produce antimicrobial peptides such as RegIIIγ and defensins when exposed to IL-22 released by CD4 TH17 cells or ILC3s. They can also respond directly to microbes, as they express TLRs and NODs and they are highly autophagic. Defects in Paneth cell function lead to reduced bacterial defense and are believed to be important in susceptibility to inflammatory bowel disease in humans. Goblet cells are a further kind of specialized epithelial cell and produce mucus in response to cytokines derived from CD4 TH2 cells or ILC2s. Mucus consists of a complex mixture of highly charged glycoproteins (mucins) and forms an essential component of immune defense in all mucosal surfaces. Its density, charge, and stickiness
Fig. 12.17 Shigella flexneri infects intestinal epithelial cells to cause bacterial dysentery. Shigella flexneri binds to M cells and is translocated beneath the gut epithelium (first panel). The bacteria infect intestinal epithelial cells from their basal surface and are released into the cytoplasm (second panel). Muramyl tripeptides containing diaminopimelic acid in the cell walls of the shigellae bind to and oligomerize the protein NOD1. Oligomerized NOD1 binds the serine/threonine kinase RIPK2 and activates the NFκB pathway (see Fig. 3.17), leading to the transcription of genes for chemokines and cytokines (third panel). Activated epithelial cells release the chemokine CXCL8, which acts as a neutrophil chemoattractant (fourth panel). IκB, inhibitor of NFκB; IκK, IκB kinase.