Interleukin-33 at the intersection of inflammation and repair

Interleukin 33 (IL-33) is a cytokine of the IL-1 family that acts as an alarmin in both innate and adaptive immunity. IL-33 is constitutively nuclear in epithelial and endothelial cells, where its activity is limited by nuclear retention. Release of IL-33 in response to cellular stress or injury can mediate type 2 immune responses or tissue repair, depending on the local tissue environment. IL-33 activity is regulated at multiple levels, including nuclear retention, oxidation, proteolytic processing, and metabolic regulation. Following its release, oxidation rapidly suppresses IL-33 activity, while mast cell and neutrophil proteases can generate smaller active fragments that target cells expressing the IL-33 ST2 receptor. Simultaneously, tissue metabolic status influences cellular responsiveness through the mTORC1 and AMPK pathways, which link metabolic capacity to effector function. These conditions may explain why IL-33 can mediate an inflammatory response, but in other circumstances, it contributes to tissue repair. Such pleiotropic properties may also underline the variability in clinical responses to IL-33/ST2-targeted therapies across various diseases. The appreciation of IL-33 as a cytokine whose activity is conditioned by its structural, redox, and metabolic environment is critical to optimizing its therapeutic potential as a target.