Role of Interleukin-3 during inflammatory bowel diseases

• Applicant: Alan Bénard, Ph.D.
• Subject Area: General and Visceral Surgery ; Immunology
• Term: from 2019 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 424983853

Intestinal homeostasis requires a controlled innate immune response to the microbiota. However, due to environmental, genetic, or microbial factors, the tolerance to the microbiota may be dysregulated leading to inflammatory bowel diseases (IBDs), pathologically characterized by an uncontrolled acute inflammation in the colon. IBDs such as ulcerative colitis or Crohn's disease are disorders of modern society, and their frequency in developed countries has been increasing since the mid-20th century. Although new treatment strategies allow to contain the disease, they are not effective in all patients. Thus, the identification of new therapeutic targets is urgently needed. IL-3, a hematopoietic growth factor, was recently described to play a key role during inflammatory diseases such as sepsis, collagen-induced arthritis or experimental autoimmune encephalitis. Thereby, IL-3 may have either beneficial or detrimental effects suggesting that IL-3 is a master regulator of inflammation. However, its contribution during inflammatory bowel diseases is still unknown. We hypothesize that IL-3 protects from colitis by promoting the recruitment of splenic neutrophils into the colon, by stimulating extramedullary hematopoiesis in spleen and by improving the membrane integrity of the colon. Our hypothesis is based on several own unpublished data showing: i) Il-3-/- mice were more susceptible to DSS-induced colitis than control mice, ii) Il-3-/- mice exhibited a stronger inflammation in colon after 7 days of DSS, iii) IL-3 promoted the recruitment of splenic neutrophils into the colon at the beginning of DSS-induced colitis, iv) a new non-hematopoietic population expressing IL-3 in the colon, v) Il-3-/- mice exhibited reduced amount of neutrophils in spleen, but not in bone marrow, after 1 and 7 days of DSS, vi) the presence of IL-3-expressing IRA B cells in spleen during colitis and vii) the expression of CD123, the IL-3 receptor alpha chain, by colonic epithelial cells. This project is important and innovative for many reasons. First, it is based on a solide phenotype in vivo showing clearly a strong impact of IL-3 during colitis. Second, it will characterize a new population that expresses IL-3. Third, it will highlight new functions of IL-3, a cytokine that is poorly studied during inflammation. Fourth, it has a clear translational potential.

• DFG Programme: Research Grants