Progressive IL-13 signaling promotes inflammation-associated liver fibrosis via IL-13RA2/MEK/ERK activation in Schistosoma japonicum infection

Progressive IL-13 signaling is closely associated with liver fibrosis. Among fibrotic diseases, liver fibrosis induced by Schistosoma japonicum in advanced schistosomiasis is the primary driver of portal hypertension, which is the leading cause of mortality in affected patients. RNA sequencing analysis of human hepatic stellate cells revealed that IL-13RA2 was markedly upregulated in activated hepatic stellate cells and enriched in the cytokine-receptor interaction pathways, suggesting a potential role for IL-13RA2 in hepatic stellate cell activation and fibrosis progression. Based on these findings, we aimed to investigate whether IL-13RA2 also contributes to liver fibrosis during Schistosoma japonicum infection. In this study, we established a murine model of Schistosoma japonicum infection. Compared with IL-13RA1, IL-13RA2 expression was significantly increased at week 9 post-infection in mice. IL-13RA2 was enriched within fibrotic regions and increased in parallel with collagen accumulation and stellate cell activation. The phosphorylation levels of MEK and ERK changed in parallel with IL-13RA2 abundance. Furthermore, overexpression of IL-13RA2 markedly accelerated hepatic fibrogenesis, while knockdown of IL-13RA2 attenuated liver fibrosis induced by schistosomiasis via the MEK/ERK pathway. Hence, IL-13RA2 may represent an effective and promising therapeutic target for the attenuation of liver fibrosis.