Figure 3. Spectrum of IL-33 biology.

A model of the spectrum of IL-33 effects on tissue during beneficial and pathologic immune responses, with IL-33 cellular pools increasing from left to right. (Homeostasis, Blue) IL-33 is present in a restricted subset of cells and cooperates with unknown signals to maintain tissue integrity, limit excess inflammation and promote tissue adaptation to remodeling and other physiologic stressors. (Amplification, Purple) During acute tissue injury and damage, IL-33 synergizes with other epithelial cytokines and lymphokines to promote tissue homeostasis and repair (stroke, myocardial infarction, wounding). Helminths elicit similar responses. With repetitive tissue damage, IL-33 pools increase, regulatory mechanisms are suppressed, inflammation is amplified and fibrosis ensues (sclerosis, cirrhosis, allergic disease). (Conversion, Red) Generation of IL-12 and other inflammatory signals promotes IL-33 signaling on inflammatory cells that are normally unresponsive, while repressing type 2-associated responses. Activation of this pathway promotes beneficial responses to infection and possibly vaccination, and may support anti-cancer immune responses in certain settings. With chronic unresolved inflammation, however, tissue IL-33 increases and ultimately contributes to tissue damage (COPD, autoimmune diseases).