Liver inflammation, a common extraintestinal manifestation of inflammatory bowel disease (IBD), was reported to unexpectedly precede ileitis onset in SAMP1/YitFc (SAMP) mice, a spontaneous model of IBD. We hypothesized that since SAMP possess an inherent epithelial barrier defect that can facilitate bacterial translocation, ultimately into the liver, toll-like receptor (TLR) activation of resident immune cells may occur, leading to liver inflammation. To test this, SAMP X MyD88KO mice were generated and liver inflammation assessed. TLRs were measured by qPCR and TLR9+ cells identified by FACS in isolated non-parenchymal liver cells (NPLs). Cytokines were measured by ELISA from NPLs +/- a TLR9 agonist, and SAMP treated with a TLR9 agonist or antagonist evaluated. Deletion of MyD88 resulted in complete amelioration of SAMP liver inflammation as early as 4, and up to 40, wks vs age-matched WT SAMP (both p<0.001). TLR9 mRNA levels were highest for TLR expression in SAMP vs AKR (parental) control livers (↑2.4-fold, p<0.001) and TLR9 expressed in both NPL F4/80+ MΦs and CD4+ T cells, with specific TLR9 activation modulating TNF, IL-12, and IL-10 (p<0.05). Finally, administration of a TLR9 agonist exacerbated (p<0.001), while a TLR9 antagonist ameliorated, SAMP liver inflammation (vs vehicle, p<0.05). These data indicate a pivotal role for TLR9 in the pathogenesis of liver inflammation in ileitis-prone SAMP mice and suggest its importance in hepatic involvement in patients with IBD.
- Copyright © 2013 by The American Association of Immunologists, Inc.