Inhibition of Interleukin 10 receptor signaling induces microbiota-dependent chronic colitis in Apolipoprotein E deficient mice (MUC5P.754)

Abstract

Abstract Apolipoprotein E (ApoE), a secreted protein, plays major role in cholesterol metabolism. ApoE is also known to exhibit anti-inflammatory properties. However, its role in the intestine, specifically during inflammation is not very clear. First, we verified upregulation of colonic ApoE transcripts in various models of murine acute and chronic colitis models. Age and gender matched ApoEKO mice and their WT littermates (n=5) were given either one or 4 weekly injections of IL-10 receptor (IL-10R) neutralizing mAb intraperitoneally and colitis development was monitored. ApoEKO mice given single injection of IL-10R mAb displayed acute colitis. Four weekly injections IL-10R mAb resulted in the development of chronic colitis as measured by colomegaly, splenomegaly and elevated colonic pro-inflammatory gene expression (TNFα, IFNγ) and histological score when compared to WT littermates. IL-10R neutralization also induced substantial levels of lipocalin 2, a general inflammatory marker in the feces, colon, and circulation in ApoEKO mice. Ablation of gut microbiota by broad-spectrum antibiotics substantially protected ApoEKO mice against IL-10R neutralization induced chronic colitis. In addition, cohousing ApoEKO mice with IL-10KO mice exaggerated spontaneous colitis (rectal prolapse) in IL-10KO mice when compared to WT suggesting ApoEKO harbor colitogenic microbiota. Collectively, our results demonstrate that ApoE plays a critical role in protecting the gut against inflammation.