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 path-ogenesis of IBDs has been investigated intensively, the etiology of IBDs remains enigmatic. Here, we report that interleukin-3 (Il-3)-deficient mice are more susceptible and exhibit increased intestinal inflammation dur-ing the early stage of experimental colitis. IL-3 is locally expressed in the colon by cells harboring a mesen-chymal stem cell phenotype and protects by promoting the early recruitment of splenic neutrophils with high microbicidal capability into the colon. Mechanistically, IL-3-dependent neutrophil recruitment involves CCL5+ PD-1high LAG-3high T cells, STAT5, and CCL20 and is sustained by extramedullary splenic hematopoi-esis. During acute colitis, Il-3-/- show, however, increased resistance to the disease as well as reduced intes-tinal inflammation. Altogether, this study deepens our understanding of IBD pathogenesis, identifies IL-3 as an orchestrator of intestinal inflammation, and reveals the spleen as an emergency reservoir for neutrophils dur-ing colonic inflammation.

Automated summary

Inflammatory bowel diseases (IBDs) have an unclear etiology despite intensive investigation into their pathogenesis. This study found that IL-3-deficient mice are more susceptible to and exhibit increased intestinal inflammation during the early stage of experimental colitis. IL-3 promotes the early recruitment of microbicidal neutrophils into the colon and is expressed locally by cells with a mesenchymal stem cell phenotype. The recruitment of neutrophils involves specific T cell subsets, STAT5, and chemokines, and is sustained by extramedullary splenic hematopoiesis. Interestingly, IL-3-deficient mice showed increased resistance to acute colitis and reduced intestinal inflammation.