PI3Kp110δ drives Crohn’s disease-like intestinal fibrosis in SHIP-/- mice

Crohn’s disease (CD) is an immune-mediated disease characterized by inflammation along the gastrointestinal tract. One in 3 people with CD will develop intestinal fibrosis requiring surgery within 10 years of diagnosis. Despite that, there are no treatments that target intestinal fibrosis directly. Our laboratory reported that mice deficient in the Src homology 2 domain-containing inositol polyphosphate 5´-phosphatase (SHIP-/-) develop spontaneous CD-like intestinal inflammation with arginase-dependent fibrosis. We also reported that increased arginase I activity in SHIP-/- macrophages was dependent on increased Class IA phosphatidylinositol 3-kinase (PI3K) p110δ activity. Based on this, we hypothesized that SHIP-/- mice develop fibrosis due to increased PI3Kp110δ activity. SHIP-/- mice were crossed with mice deficient in PI3Kp110δ activity (PI3Kp110δDA/DA). SHIP-/- PI3Kp110δDA/DA mice have reduced intestinal fibrosis compared to their SHIP-/- littermates including: reduced muscle thickening, vimentin+ mesenchymal cells, collagen deposition, arginase activity, and IL-4 levels. SHIP-/- mice were also treated with a PI3Kp110δ isoform-specific inhibitor, IC87114. Pharmacological inhibition of PI3Kp110δ activity also reduced the above parameters that are associated with intestinal fibrosis in SHIP-/- mice. Surprisingly, PI3Kp110δ deficiency or inhibition also reduced ileal inflammation and IL-1β production in the SHIP-/- ileum suggesting that PI3Kp110δ, and/or fibrosis itself, may contribute directly to inflammation. Our data suggest that SHIP-/- mice develop intestinal fibrosis that is driven by PI3Kp110δ activity. Moreover, targeting PI3Kp110δ activity may be an effective strategy to reduce intestinal fibrosis in people with CD. Importantly, there are PI3Kp110δ isoform-specific inhibitors already licensed for use in people with certain leukemias and lymphomas, so this research may be rapidly translatable into an effective therapy for intestinal fibrosis in people with CD.Medicine, Faculty ofExperimental Medicine, Division ofMedicine, Department ofGraduat