COX-expressing tuft cells initiate Crohn’s disease-like intestinal inflammation in SHIP-/- mice

Inflammatory bowel disease (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), is characterized by intestinal inflammation. Intestinal epithelial cells play a critical role in mucosal homeostasis and dysregulation of pro-inflammatory epithelial cell function could lead to the intestinal inflammation that characterizes IBD. However, we do not know the events that initiate inflammation or the cell types involved. One type of cell that may play a role is the tuft cell. Tuft cells are the only epithelial cells in the uninflamed intestine that express cyclooxygenase (COX)1 and COX2, the rate-limiting enzymes required for production of prostaglandins, like PGE2 and PGD2 which play important roles in immunity. In our research investigating the lipid phosphatase SHIP, it was discovered that tuft cells express SHIP. SHIP deficiency leads to increased PI3-kinase activity in cells resulting in increased cell proliferation, reduced apoptosis, and increased cell activation. SHIP expression is currently believed to be restricted to hematopoietic cells. However, using bone marrow transplantation, our laboratory found that tuft cells were not radiosensitive, suggesting that they are not bone-marrow derived and are not hematopoietic in origin. In addition, SHIP-deficient mice develop spontaneous Crohn’s disease-like intestinal inflammation. The onset of inflammation coincides with the developmental appearance of tuft cells. In wild type mice, tuft cells are found in the lung and ileum, both locations where SHIP-deficient mice develop spontaneous inflammation, and I found that tuft cell numbers were increased 6-fold in the inflamed ileum of SHIP-deficient mice. Based on this, I hypothesized that SHIP-deficient tuft cells may initiate or contribute to inflammation in the SHIP-deficient mouse. I found that SHIP-deficient mice had more COX1 positive cells in the ileum, more COX activity, and more PGD2 and PGE2 in full thickness ileal tissue homogenates, compared to their wild-type littermates. Finally, prophylactic inhibition of COX activity with piroxicam reduced the development of intestinal inflammation in SHIP-deficient mice whereas therapeutic treatment had little effect. This suggests that tuft cells may be critical in the initiation of spontaneous intestinal inflammation in SHIP-deficient mice and help elucidate some of the basic biology involved in the inflammation present in patients with CD.Medicine, Faculty ofExperimental Medicine, Division ofMedicine, Department ofGraduat