Abstract
BACKGROUND: ADAM17 is required for the shedding of a variety of substrates, including TNFa and ErbB ligand/receptor families. In several mouse models of intestinal injury/ regeneration, we have observed up-regulation of ADAM17 expression. In a total parenteral nutrition (TPN) model, intestine-specific ADAM17 deletion had a protective effect with preservation of epithelial cell (EC) proliferation and prevention of EC apoptosis. In this study, we used tissue-specific ADAM17KO mice to investigate the role of ADAM17 in DSSinduced injury response. METHODS: Tissue-specific ADAM17KO mice were generated by breeding ADAM17loxP/loxP mice to Villin-Cre, Villin-CreER or LysM-Cre mice. Intestinespecific (Vil-Cre and Vil-CreER) and myeloid-specific (LysM-Cre) ADAM17KO mice were viable, did not show any overt intestinal phenotype and no alteration in transepithelial resistance was observed. For DSS studies, 6-7 week old Vil-Cre;ADAM17KO, Vil-CreER;ADAM17KO, LysM-Cre;ADAM17KO and genotype control (ADAM17loxP/loxP or Cre;ADAM17loxP/+) mice were used. Daily body weights and disease activity indexed (DAI) were measured. At sacrifice, colon lengths were measured prior to tissue collection and analysis of histological scoring, IHC and qRT-PCR. RESULTS: In control mice treated with 3% DSS for 5 days and then allowed to recover for 14 days, significant increases in ADAM17 mRNA levels of 3.4 and 4.8-fold were detected at each respective time point. This indicated that ADAM17 expression was increased upon DSS-induced injury and its upregulated expression was sustained throughout the recovery period. To examine the effect of intestine-specific ADAM17-deficiency on intestinal cell responses, Vil-Cre;ADAM17KO and control mice were treated continuously with water or 2% DSS for 9 days. In untreated mice, no evidence of spontaneous DAI or inflammation was observed. By contrast, DSS-treated Vil-Cre;ADAM17KOmice showed rapidweight loss and amarked increase in DAI scores when compared to DSS-treated controls. Additionally, reduced colon lengths and more severe histological scores confirmed that Vil-Cre;ADAM17KO mice were more susceptible to DSS injury. However, when the same DSS experiment was performed using myeloid-specific LysM-Cre;ADAM17KO mice, no increase in DSS susceptibility was observed. To further define the requirement for ADAM17 in the epithelial repair, Vil-Cre;ADAM17KO mice were treated with 2% DSS for 5 days and then allowed to recover for 14 days. DSS-treated Vil-Cre;ADAM17KO mice showed DSS sensitivity but had a delayed repair. Tamoxifen-inducible (TX) Vil-CreER;ADAM17KO mice are now being used to determine the requirement for epithelial ADAM17 signaling in the intestinal recovery phase. CONCLUSIONS: Cell-autonomous ADAM17 signaling in epithelial cells is protective against DSS injury, whereas ADAM17 signaling exacerbates epithelial atrophy in the TPN model.
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