Fig. 5
Spatiotemporal regulation of IL-23 expression in mononuclear phagocytes during acute and chronic gut inflammation. A In acute inflammation during infection, IL-23 expression is limited to cDCIL-23, which is located within GALTs, such as ILFs and CPs. Although macrophages in the lamina propria may also become activated during infection, their production of IL-23 is typically inhibited by IL-10 and Lag3 from Tregs, as well as potentially other environmental factors. Consequently, after elimination of mucosal pathogens, the immune response mediated by type 17 immune cells swiftly returns to baseline levels. B In IBD, genetic and environmental factors alter the functionality of macrophages in the lamina propria, either directly or through pathways involving IL-10 and Lag3 from Tregs. These alterations lead to excessive activation of macrophages, which become hypersensitive to CD40 and TLR stimulation from activated T cells and the gut microbiota, respectively. As a result, these macrophages produce large amounts of IL-23. Elevated IL-23 then promotes the differentiation of pathogenic Th17 cells, which drive intestinal inflammation and compromise the barrier function of IECs. IL-23 also impairs the suppressive functions of Tregs, reducing their ability to regulate macrophage activity. This cascade creates a positive feedback loop between T cells and macrophages through the CD40‒IL-23 axis. Continuous stimulation from the gut microbiota, due to impaired barrier function, further augments chronic inflammation driven by type 17 immune responses
