title: SHIP-deficient mice develop spontaneous intestinal inflammation and arginase-dependent fibrosis.
abstract: Intestinal fibrosis is a serious complication of Crohn's disease (CD) that can lead to stricture formation, which requires surgery. Mechanisms underlying intestinal fibrosis remain elusive because of a lack of suitable mouse models. Herein, we describe a spontaneous mouse model of intestinal inflammation with fibrosis and the profibrotic role of arginase I. The Src homology 2 domain-containing inositol polyphosphate 5'-phosphatase-deficient (SHIP(-/-)) mice developed spontaneous discontinuous intestinal inflammation restricted to the distal ileum starting at the age of 4 weeks. Mice developed several key features resembling CD, including inflammation and fibrosis. Inflammation was characterized by abundant infiltrating Gr-1-positive immune cells, granuloma-like immune cell aggregates that contained multinucleated giant cells, and a mixed type 2 and type 17 helper T-cell cytokine profile. Fibrosis was characterized by a thickened ileal muscle layer, collagen deposition, and increased fibroblasts at the sites of collagen deposition. SHIP(-/-) ilea had increased arginase activity and arginase I expression that was inversely proportional to nitrotyrosine staining. SHIP(-/-) mice were treated with the arginase inhibitor S-(2-boronoethyl)-l-cysteine, and changes in the disease phenotype were measured. Arginase inhibition did not affect the number of immune cell infiltrates in the SHIP(-/-) mouse ilea; rather, it reduced collagen deposition and muscle hyperplasia. These findings suggest that arginase activity is a potential target to limit intestinal fibrosis in patients with CD.
authors.affiliation: Division of Gastroeneterology, Department of Pediatrics, BC Children's Hospital, Vancouver, British Columbia, Canada.
authors.forename: Keith W
authors.initials: KW
authors.lastname: McLarren
authors.forename: Alexandra E
authors.initials: AE
authors.lastname: Cole
authors.forename: Shelley B
authors.initials: SB
authors.lastname: Weisser
authors.forename: Nicole S
authors.initials: NS
authors.lastname: Voglmaier
authors.forename: Victoria S
authors.initials: VS
authors.lastname: Conlin
authors.forename: Kevan
authors.initials: K
authors.lastname: Jacobson
authors.forename: Oana
authors.initials: O
authors.lastname: Popescu
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Boucher
authors.forename: Laura M
authors.initials: LM
authors.lastname: Sly
mesh_terms: D000818:Animals; D001119:Arginase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D001897:Boronic Acids / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D005355:Fibrosis / Q000201:enzymology* / Q000209:etiology / Q000473:pathology*; D006965:Hyperplasia / Q000378:metabolism / Q000473:pathology; D007082:Ileum / Q000378:metabolism / Q000473:pathology; D007124:Immunoenzyme Techniques; D007249:Inflammation / Q000201:enzymology / Q000209:etiology / Q000473:pathology*; D000072181:Inositol Polyphosphate 5-Phosphatases; D007410:Intestinal Diseases / Q000201:enzymology / Q000209:etiology / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D010744:Phosphoric Monoester Hydrolases / Q000502:physiology*; D019707:Receptors, Chemokine / Q000378:metabolism; D058504:Th17 Cells
chemical_list: C425062:(2-boronoethyl)-cysteine; D001897:Boronic Acids; D016207:Cytokines; C503133:Gr-1 protein, mouse; D019707:Receptors, Chemokine; D010744:Phosphoric Monoester Hydrolases; D000072181:Inositol Polyphosphate 5-Phosphatases; D001119:Arginase