IL-3 orchestrates ulcerative colitis pathogenesis by controlling the development and the recruitment of splenic reservoir neutrophils

Inflammatory bowel diseases (IBDs) are a global health issue with an increasing incidence. Although the pathogenesis of IBDs has been investigated intensively over the past decades, the etiology of IBDs remains enigmatic. Here we report that interleukin-3 (Il-3) deficient mice were more susceptible to experimental colitis and exhibited higher intestinal inflammation during the early stage of colitis. IL-3 protected by promoting the early recruitment of splenic neutrophils into the colon with high microbicidal capability, mechanistically involving CCL5+ T cells and CCL20. IL-3 was locally expressed in the colon by cells harboring a mesenchymal stem cell phenotype and neutrophil recruitment into the colon was sustained by IL-3-dependent splenic extramedullary hematopoiesis. Moreover, mucosal expression of IL-3 and IL-3 receptor were increased in patients with IBDs, their expression being associated with higher intestinal inflammation. Altogether, our results identify a new IL-3-expressing cell as an orchestrator of rapid deployment of inflammatory splenic neutrophils into the colon and reveals the spleen as an emergency reservoir for neutrophils during colonic inflammation.