Interleukin‐33 facilitates liver regeneration through serotonin‐involved gut‐liver axis

Background and Aims Insufficient liver regeneration causes post-hepatectomy liver failure and small-for-size syndrome. Identifying therapeutic targets to enhance hepatic regenerative capacity remains urgent. Recently, increased IL-33 was observed in patients undergoing liver resection and in mice after partial hepatectomy (PHx). The present study aims to investigate the role of IL-33 in liver regeneration after PHx and to elucidate its underlying mechanisms. Approach and Results We performed PHx in IL-33(-/-), suppression of tumorigenicity 2 (ST2)(-/-), and wild-type control mice, and found deficiency of IL-33 or its receptor ST2 delayed liver regeneration. The insufficient liver regeneration could be normalized in IL-33(-/-) but not ST2(-/-) mice by recombinant murine IL-33 administration. Furthermore, we observed an increased level of serotonin in portal blood from wild-type mice, but not IL-33(-/-) or ST2(-/-) mice, after PHx. ST2 deficiency specifically in enterochromaffin cells recapitulated the phenotype of delayed liver regeneration observed in ST2(-/-) mice. Moreover, the impeded liver regeneration in IL-33(-/-) and ST2(-/-) mice was restored to normal levels by the treatment with (+/-)-2,5-dimethoxy-4-iodoamphetamine, which is an agonist of the 5-hydroxytrytamine receptor (HTR)2A. Notably, in vitro experiments demonstrated that serotonin/HTR2A-induced hepatocyte proliferation is dependent on p70S6K activation. Conclusions Our study identified that IL-33 is pro-regenerative in a noninjurious model of liver resection. The underlying mechanism involved IL-33/ST2-induced increase of serotonin release from enterochromaffin cells to portal blood and subsequent HTR2A/p70S6K activation in hepatocytes by serotonin. The findings implicate the potential of targeting the IL-33/ST2/serotonin pathway to reduce the risk of post-hepatectomy liver failure and small-for-size syndrome.