Altered macrophage function contributes to colitis in mice defective in the phosphoinositide-3 kinase subunit p110δ

Document Type

Journal Article

Publication Date

1-1-2010

Journal

Gastroenterology

Volume

139

Issue

5

DOI

10.1053/j.gastro.2010.07.008

Keywords

Enteric Microbiota; Inflammatory Bowel Diseases; Innate Immunity; PI3-Kinase

Abstract

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 p110δD910A/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 p110δD910A/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, p110δD910A/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 p110δD910A/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 p110δD910A/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. © 2010 by the AGA Institute.

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