The absence of functional PI3Kγ prevents leukocyte recruitment and ameliorates DSS-induced colitis in mice

• Published in: Immunology letters 2010-06, Vol.131 (1), p.33-39
• Main Authors: van Dop, Willemijn A, Marengo, Stefano, te Velde, Anje A, Ciraolo, Elisa, Franco, Irene, ten Kate, Fiebo J, Boeckxstaens, Guy E, Hardwick, James C, Hommes, Daan W, Hirsch, Emilio, van den Brink, Gijs R
• Format: Article
• Language: English
• Subjects: Allergy and Immunology; Colitis; Cytokines; Leukocyte migration; Mucosal immunology
• ISSN: 0165-2478; 1879-0542
• DOI: 10.1016/j.imlet.2010.03.008

Abstract Phosphatidylinositol-3-kinase gamma (PI3Kγ) is the major PI3K that is activated in response to chemoattractants. It is responsible for the migration of leukocytes from the bloodstream to sites of injury or infection. Constant migration of new leukocytes to the intestinal mucosa may be an important factor in maintenance of inflammation and tissue damage in inflammatory bowel disease (IBD). Reducing this influx, for example by inhibition of PI3Kγ, might therefore be a potential goal for therapy. Here we investigated the role of PI3Kγ in the migration of leukocytes to sites of intestinal inflammation. We induced colitis in mice with a point mutation that inactivates PI3Kγ enzymatic activity (‘kinase-dead’) by oral administration of dextran sodium sulphate (DSS). Mice were treated with 1.5% DSS for 1 week and effects on cytokine production, leukocyte recruitment and disease severity were examined. Both clinical and histological parameters showed that the severity of colitis was significantly reduced in PI3Kγ-kinase-dead mice compared to controls. Although mutant mice had a less severe colitis than controls they produced significantly more pro-inflammatory Th1 cytokines such as Il-12, Tnfα and Ifnγ and more Il-10. PI3Kγ mutant mice showed increased numbers of resident macrophages and T cells in the colonic lamina propria in an unstressed condition but failed to recruit new leukocytes to the mucosa upon treatment with DSS despite the increased cytokine levels. These results suggest that PI3Kγ plays a critical role in lamina propria leukocyte trafficking and that loss of PI3Kγ-activity ameliorates DSS-induced colitis in mice.