Phosphatidylinositol 3-kinase p110δ drives intestinal fibrosis in SHIP deficiency.
Mucosal Immunol
; 12(5): 1187-1200, 2019 09.
Article
in En
| MEDLINE
| ID: mdl-31358861
ABSTRACT
Crohn's disease is an immune-mediated disease characterized by inflammation along the gastrointestinal tract. Fibrosis requiring surgery occurs in one-third of people with Crohn's disease but there are no treatments for intestinal fibrosis. Mice deficient in the SH2 domain-containing inositolpolyphosphate 5'-phosphatase (SHIP), a negative regulator of phosphatidylinositol 3-kinase (PI3K) develop spontaneous Crohn's disease-like intestinal inflammation and arginase I (argI)-dependent fibrosis. ArgI is up-regulated in SHIP deficiency by PI3Kp110δ activity. Thus, we hypothesized that SHIP-deficient mice develop fibrosis due to increased PI3Kp110δ activity. In SHIP-deficient mice, genetic ablation or pharmacological inhibition of PI3Kp110δ activity reduced intestinal fibrosis, including muscle thickening, accumulation of vimentin+ mesenchymal cells, and collagen deposition. PI3Kp110δ deficiency or inhibition also reduced ileal inflammation in SHIP-deficient mice suggesting that PI3Kp110δ may contribute to inflammation. Targeting PI3Kp110δ activity may be an effective strategy to reduce intestinal fibrosis, and may be particularly effective in the subset of people with Crohn's disease, who have low SHIP activity.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Class Ia Phosphatidylinositol 3-Kinase
/
Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases
/
Inflammation
/
Intestines
Type of study:
Prognostic_studies
Limits:
Animals
Language:
En
Journal:
Mucosal Immunol
Journal subject:
ALERGIA E IMUNOLOGIA
Year:
2019
Document type:
Article
Affiliation country:
Canada