NF˜BTLRNODsCCL2CCL1IL-6CXCL1CXCL8IL-1IL-1IL-18I˜BTLR-5CCL20defensinstightjunctionslysosomephagosomephagophorecaspaseNOD-2TLRs, NOD1, and NOD2 activate NF˜B, inducing the epithelial cell to express in˜ammatory cytokines, chemokines, and other mediators. These recruit and activate neutrophils, macrophages, and dendritic cells Bacteria are recognized by TLRs on cell surface or in intracellular vesicles Bacteria or their products directly entering the cytosol are recognized by NOD1 and NOD2 Activation of in˜ammasome induces production of IL-1, IL-18 which activate myeloid cells and increase barrier integrity Bacteria in cytoplasm or escaping from phagosome are taken into forming autophagosome and destroyed after fusion with lysosome Intracellular infection triggers formation of in˜ammasome Destruction of bacteria in autophagosome
Fig. 12.15 Epithelial cells have a crucial role in innate defense against pathogens. TLRs are present in intracellular vesicles or on the basolateral or apical surfaces of epithelial cells, where they recognize different components of invading bacteria. Cytoplasmic NOD1 and NOD2 detect cell‑wall peptides from bacteria. TLRs and NODs activate NFκB (see Fig. 3.15), inducing epithelial cells to produce CXCL8, CXCL1 (GROα), CCL1, and CCL2, which attract neutrophils and macrophages, CCL20, which attracts dendritic cells, and IL‑1 and IL‑6 that activate macrophages. Many types of cell damage can activate inflammasome (see Section 3‑9) that activates pro‑caspase 1 and produces IL‑1 and IL‑18. Bacteria that invade the epithelial‑cell cytoplasm or escape into the cytosol from phagosomes can induce autophagy. The organisms become ubiquitinated, leading to the recruitment of adaptor proteins that attract the phagophore, forming an autophagosome. Fusion with lysosomes then leads to destruction of the cargo within the autophagosome. NOD2 can also trigger autophagosome formation by binding directly to adaptor proteins, including the Crohn’s disease‑associated molecule ATGL16L1.
Typhimurium adheres to and enters M cells, which it then kills by causing apoptosis (top left). It then can infect macrophages and gut epithelial cells. TLR‑5 expressed by the epithelial basal membrane can bind salmonella flagellin, activating the NFκB pathway. After uptake by macrophages in the lamina propria, invasive Salmonella induces caspase 1 activation, promoting production of IL‑1 and IL‑8. CXCL8 is also produced by the infected macrophages, and together these mediators recruit and activate neutrophils (lower left panel). Salmonellae can also invade gut epithelial cells directly by adherence of fine threadlike protrusions on the luminal epithelial surface called fimbriae (top middle panel). The cell processes extended between epithelial cells by mononuclear phagocytes may be infected by salmonellae in the lumen and thus effectively breach the epithelial layer (top right panel). Dendritic cells in lamina propria may become infected from infected macrophages and carry them to the draining mesenteric lymph node to prime the adaptive immune response (lower right panel). If containment processes in the lymph node fail, Salmonella can invade beyond the intestine and its lymphoid tissues and enter the bloodstream to cause systemic infection.