IL-18 promotes pancreatic fibrosis via release of IL-4 from pancreatic stellate cells and induces macrophage M2 polarization

Chronic Pancreatitis (CP) is a progressive inflammatory disease leading to fibrosis. The role of interleukin-18 (IL-18), an inflammation-associated cytokine, in CP, especially its interactions with pancreatic stellate cells (PSCs) and macrophages, remains unclear. Human CP tissues and caerulein-induced CP models in mice were used to explore the role of IL-18 in fibrosis. Histopathological analysis, immunofluorescence, and in vitro co-culture systems were employed to identify cellular targets and downstream signaling of IL-18. IL-18 expression was elevated in CP pancreata, correlating with the severity of fibrosis. Deletion of IL-18Rα reduced fibrosis, PSC activation, and macrophage M2 polarization in CP mice. IL-18 directly stimulated PSCs to secrete interleukin-4 (IL-4), which induced M2 polarization of macrophages, exacerbating fibrosis. Inhibition of IL-4 alleviated fibrosis and M2 polarization. IL-18 plays a critical role in driving pancreatic fibrosis by modulating PSCs-macrophage interactions, providing a potential therapeutic target to disrupt the fibrotic process in CP.