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.