Microbial Sensing by the Intestinal Epithelium in the Pathogenesis of Inflammatory Bowel Disease
Figure 3
The innate immune system during intestinal inflammation. A defect in the intestinal epithelium, possibly genetically driven, causing tissue destruction, increased epithelial permeability and inflammation permits bacteria and their antigens, such as LPS and MDP, to penetrate through the epithelial monolayer. The bacterial wall component, peptidoglycan, is cut by intracellular endosomes to MDP, that can activate the NALP3 inflammasome. As a consequence, pro-IL1β and pro-IL18 are processed to active molecules, what triggers proinflammatory conditions in the epithelium. LPS binding to its receptor, TLR4, results in the activation of NF-B and, subsequently, in increased expression of cytokines, such as TNF, IFN or IL6. MDP activates NOD2 directly, causing increased NF-B activity. In addition to elevated cytokine levels, NOD2 also induces the expression of antimicrobial peptides, such as defensins. Bacteria, such as E. coli or Listeria monocytogenes, can activate the autophagosome that plays a key role for inactivating invasive bacteria and other pathogenic components. The autophagy machinery is also regulated by NOD2 activity. Cytokines, such as IFN have been shown to increase the activity of PTPN2 that, in turn, downregulates proinflammatory signalling. Dysfunction of PTPN2 results in an impaired epithelial barrier function and elevated secretion of proinflammatory cytokines. Malfunction of the innate immune response mechanisms in the gastrointestinal tract, possibly genetically triggered, causes tissue destruction, increased apoptosis of intestinal epithelial cells, elevated epithelial permeability, and, finally, establishes a chronic inflammatory state in the intestine.
