The role of interleukin-33 in organ fibrosis

Summary Interleukin (IL)-33 is highly expressed in the nucleus of cells present at barrier sites and signals via the ST2 receptor. IL-33 signalling via ST2 is essential for return to tissue homeostasis after acute inflammation, promoting fibrinogenesis and wound healing at injury sites. However, this wound-healing response becomes aberrant during chronic or sustained inflammation, leading to transforming growth factor beta (TGF-β) release, excessive extracellular matrix deposition, and fibrosis. This review addresses the role of the IL-33 pathway in fibrotic diseases of the lung, liver, gastrointestinal tract, skin, kidney and heart. In the lung and liver, IL-33 release leads to the activation of pro-fibrotic TGF-β, and in these sites, IL-33 has clear pro-fibrotic roles. In the gastrointestinal tract, skin, and kidney, the role of IL-33 is more complex, being both pro-fibrotic and tissue protective. Finally, in the heart, IL-33 serves cardioprotective functions by favouring tissue healing and preventing cardiomyocyte death. Altogether, this review indicates the presence of an unclear and delicate balance between resolving and pro-fibrotic capabilities of IL-33, which has a central role in the modulation of type 2 inflammation and fibrosis in response to tissue injury.