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

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 p110 delta subunit of phosphoinositide 3-kinase (PI3K p110 delta(D910A/D910A)) revealed defects in Band 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 p110 delta(D910A/D910A) mice were evaluated for colonic inflammation and innate immune dysfunction. Colonic p110 delta 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, p110 delta(D910A/D910A) mice were back-crossed to IL-10(-/-) mice. RESULTS: A mild spontaneous colitis was shown in PI3K p110 delta(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 p110 delta(D910A/D910A) macrophages, augmented toll-like receptor signaling and defective bactericidal activity were observed. Consistent with an important homeostatic role for PI3K p110 delta, wild-type mice raised in a germ-free environment markedly up-regulated colonic PI3K p110 delta expression with the introduction of the enteric microbiota; however, colitis-prone IL-10(-/-) mice did not. Moreover, PI3K p110 delta(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 p110 delta in maintaining mucosal homeostasis and could provide insight into the pathogenesis of human inflammatory bowel disease.