Abstract
Peripheral serotonin (5-HT) is mainly generated from the gastrointestinal tract and taken up and stored by platelets in the circulation. Although the gut is recognized as a major immune organ, how intestinal local immune responses control whole-body physiology via 5-HT remains unclear. Here, we show that intestinal inflammation enhances systemic platelet activation and blood coagulation. Intestinal epithelium damage induces elevated levels of the alarm cytokine interleukin-33 (IL-33), leading to platelet activation via promotion of gut-derived 5-HT release. More importantly, we found that loss of intestinal epithelial-derived IL-33 lowers peripheral 5-HT levels, resulting in compromised platelet activation and hemostasis. Functionally, intestinal IL-33 contributes to the recruitment of neutrophils to sites of acute inflammation by enhancing platelet activities. Genetic deletion of intestinal IL-33 or neutralization of peripheral IL-33 protects animals from lipopolysaccharide endotoxic shock through attenuated neutrophil extravasation. Therefore, our data establish a distinct role of intestinal IL-33 in activating platelets by promoting 5-HT release for systemic physiology and inflammation.