Fig. 3

The amplification loops of IL-33 in CNS. (1) Autocrine loop in astrocytes: IL-33 is inducible by inflammatory stimuli in astrocytes. IL-33 induces the release of pro-inflammatory cytokines from astrocytes. Pro-inflammatory cytokines stimulate astrocytes to release more IL-33. (2) IL-33 secretion by astrocytes activates other immune cells to release pro-inflammatory mediators in the brain, and pro-inflammatory mediators further promote the release of IL-33 from these cells. (i) Amplification loop between astrocytes and microglia: pro-inflammatory mediators produced by IL-33-activated microglia, such as IL-1β, TNF-α, GMF, ROS, NO, and CCL2, which in turn activate microglia to secret more pro-inflammatory mediators and secret high levels of IL-33 from astrocytes and microglia. (ii) Amplification loop between GMF and IL-33 in astrocytes and mast cells: GMF induces the release of inflammatory mediators IL-33, ROS, and CCL2 in astrocytes and mast cells. IL-33 also augments the release of GMF-mediated IL-1β, TNF-α, ROS, and CCL2 in astrocytes and mast cells. (iii) Amplification loop between IL-1β and IL-33 in microglia and oligodendrocytes: IL-33 induces the production of IL-1β in microglia through IL-33/ST2 pathway, and IL-1β activates oligodendrocytes in turn to secret high levels of IL-33