Cell Reports (Jun 2023)

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

  • Alan Bénard,
  • Anke Mittelstädt,
  • Bettina Klösch,
  • Karolina Glanz,
  • Jan Müller,
  • Janina Schoen,
  • Björn Nüse,
  • Maximilian Brunner,
  • Elisabeth Naschberger,
  • Michael Stürzl,
  • Jochen Mattner,
  • Luis E. Muñoz,
  • Kai Sohn,
  • Robert Grützmann,
  • Georg F. Weber

Journal volume & issue
Vol. 42, no. 6
p. 112637

Abstract

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Summary: Inflammatory bowel diseases (IBDs) are a global health issue with an increasing incidence. Although the pathogenesis 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 during the early stage of experimental colitis. IL-3 is locally expressed in the colon by cells harboring a mesenchymal 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 hematopoiesis. During acute colitis, Il-3−/− show, however, increased resistance to the disease as well as reduced intestinal 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 during colonic inflammation.

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