IL-33/ST2 signaling in pain and itch: Cellular and molecular mechanisms and therapeutic potentials

Pain is a cardinal feature of many diseases. Chronic pain poses heavy burdens to the suffering patients, both physically and mentally. However, current mainstream medications for chronic pain, including opioids, antidepressants and non-steroid anti-inflammatory drugs are sometimes inefficient for chronic pain management and may cause side effects that limit long term usage. IL-33 belongs to IL-1 cytokine family and it exerts biological activities through binding to its specific receptor ST2. IL-33/ST2 signaling is very important in both innate and adaptive immunity. Emerging evidence indicates IL-33/ST2 signaling regulates pain in both immune and somatosensory systems through promoting neuro-immune or neuron-glia crosstalk, neuroinflammation and neuronal hyperexcitability. Some very latest studies indicate a vital part of IL-33/ST2 in mediating chronic itch. This work aims to overview the existing knowledge regarding the mechanisms of IL-33/ST2 involvement in pain and itch conditions, considering their potential similarities. We also summarized some key findings obtained from clinical studies. The targeting of IL-33/ST2 signaling holds promise for the development of novel therapeutic modalities in the management of pain and itch.