Figure 1.

IL-33 regulates the signaling of microglial cells and depression. The N-terminal nuclear domain of IL-33 is located at amino acids 1–78 of the IL-33 protein and has transcriptional inhibition activity. The IL-1-like cytokine domain of IL-33 is located at amino acids 111–270 and has inflammatory activity by binding to ST2L. External stress, emotional stress, and inflammation stimulation (PAMPs) in the body increase the release of IL-33 in microglial cells in the paraventricular nucleus of the hypothalamus and prefrontal cortex. After precursor IL-33 is released, it is cleaved into its active form by cysteine proteases 1 and 5, which are activated by inflammasomes in the brain. IL-33 with its receptor ST2 and IL1RAcP formed a heterodimeric receptor complex which activates downstream Myd88 and MAPK, activates mTOR through AKT, activates NF-κB in the nucleus, promotes microglial mitochondrial activity, and polarizes microglia into M2 macrophages. At the same time, it activates the synaptic recruitment of scaffold protein PSD-95 and the expression of muscle enhancer factor 2C (MEF2C), promotes the formation of functional excitatory synapses in hippocampal CA1 neurons, increases neural transmission, promotes synaptic remodeling and numbers, and reduces the risk of depression.