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Altered Macrophage Function Contributes to Colitis in Mice Defective in the Phosphoinositide-3 Kinase Subunit p110δ

2010; Elsevier BV; Volume: 139; Issue: 5 Linguagem: Inglês

10.1053/j.gastro.2010.07.008

1528-0012

Jennifer K. Uno, Kavitha N. Rao, Katsuyoshi Matsuoka, Shehzad Z. Sheikh, Taku Kobayashi, Fengling Li, Erin C. Steinbach, Antonia R. Sepulveda, Bart Vanhaesebroeck, R. Balfour Sartor, Scott E. Plevy,

Immune Cell Function and Interaction

Background & Aims Innate immune responses are crucial for host defense against pathogens but need to be tightly regulated to prevent chronic inflammation. Initial characterization of mice with a targeted inactivating mutation in the p110δ subunit of phosphoinositide 3-kinase (PI3K p110δ D910A/D910A ) revealed defects in B- and T-cell signaling and chronic colitis. Here, we further characterize features of inflammatory bowel diseases in these mice and investigate underlying innate immune defects. Methods Colons and macrophages from PI3K p110δ D910A/D910A mice were evaluated for colonic inflammation and innate immune dysfunction. Colonic p110δ messenger RNA expression was examined in interleukin (IL)-10 −/− and wild-type germ-free mice during transition to a conventional microbiota. To assess polygenic impact on development of colitis, p110δ D910A/D910A mice were backcrossed to IL-10 −/− mice. Results A mild spontaneous colitis was shown in PI3K p110δ D910A/D910A mice at 8 weeks, with inflammation increasing with age. An inflammatory mucosal and systemic cytokine profile was characterized by expression of IL-12/23. In PI3K p110δ D910A/D910A macrophages, augmented toll-like receptor signaling and defective bactericidal activity were observed. Consistent with an important homeostatic role for PI3K p110δ, wild-type mice raised in a germ-free environment markedly up-regulated colonic PI3K p110δ expression with the introduction of the enteric microbiota; however, colitis-prone IL-10 −/− mice did not. Moreover, PI3K p110δ D910A/D910A mice crossed to IL-10 −/− mice developed severe colitis at an early age. Conclusions This study describes a novel model of experimental colitis that highlights the importance of PI3K p110δ in maintaining mucosal homeostasis and could provide insight into the pathogenesis of human inflammatory bowel disease.