Loss of ADAM17-Mediated Tumor Necrosis Factor Alpha Signaling in Intestinal Cells Attenuates Mucosal Atrophy in a Mouse Model of Parenteral Nutrition

Total parenteral nutrition (TPN) is commonly used clinically to sustain patients; however, TPN is associated with profoundmu-cosal atrophy, which may adversely affect clinical outcomes. Using a mouse TPNmodel, removing enteral nutrition leads to de-creased crypt proliferation, increased intestinal epithelial cell (IEC) apoptosis and increased mucosal tumor necrosis factor al-pha (TNF-) expression that ultimately produces mucosal atrophy. Upregulation of TNF- signaling plays a central role in mediating TPN-inducedmucosal atrophy without intact epidermal growth factor receptor (EGFR) signaling. Currently, the mechanism and the tissue-specific contributions of TNF- signaling to TPN-inducedmucosal atrophy remain unclear. ADAM17 is an ectodomain sheddase that canmodulate the signaling activity of several cytokine/growth factor receptor families, including the TNF-/TNF receptor and ErbB ligand/EGFR pathways. Using TPN-treated IEC-specific ADAM17-deficient mice, the present study demonstrates that a loss of soluble TNF- signaling from IECs attenuates TPN-inducedmucosal atrophy. Importantly, this response remains dependent on the maintenance of functional EGFR signaling in IECs. TNF- blockade in wild-type mice receiving TPN confirmed that soluble TNF- signaling is responsible for downregulation of EGFR signaling in IECs. These re-sults demonstrate that ADAM17-mediated TNF- signaling from IECs has a significant role in the development of the proin-flammatory state andmucosal atrophy observed in TPN-treated mice. Although total parenteral nutrition (TPN) is an essential ther-apy for patients who cannot tolerate enteral nutrition, ther