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

Abstract

e Total parenteral nutrition (TPN) is commonly used clinically to sustain patients; however, TPN is associated with profound mucosal atrophy, which may adversely affect clinical outcomes. Using a mouse TPN model, removing enteral nutrition leads to decreased crypt proliferation, increased intestinal epithelial cell (IEC) apoptosis and increased mucosal tumor necrosis factor alpha (TNF-␣) expression that ultimately produces mucosal atrophy. Upregulation of TNF-␣ signaling plays a central role in mediating TPN-induced mucosal atrophy without intact epidermal growth factor receptor (EGFR) signaling. Currently, the mechanism and the tissue-specific contributions of TNF-␣ signaling to TPN-induced mucosal atrophy remain unclear. ADAM17 is an ectodomain sheddase that can modulate 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-induced mucosal 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 results demonstrate that ADAM17-mediated TNF-␣ signaling from IECs has a significant role in the development of the proinflammatory state and mucosal atrophy observed in TPN-treated mice.A lthough total parenteral nutrition (TPN) is an essential therapy for patients who cannot tolerate enteral nutrition, there are numerous and significant clinical sequelae associated with TPN treatment (1). These clinical complications, which include altered immunological responses, hepatic dysfunction, metabolic derangements, endotoxemia, bacterial infections, and sepsis, can delay or make it difficult to wean patients back onto enteral nutrition. Several studies have indicated that early TPN administration in critically ill patients is associated with worsened clinical outcomes and increased rates of septicemia, often from enterically derived organisms (1, 2). These issues clearly highlight that a more detailed understanding of the underlying mechanisms of TPN-related intestinal complications is needed both to improve the selection and administration of TPN to patients and for the development of new therapeutic options for patients dependent on TPN.The mouse model of TPN represents an ideal system to study signal transduction pathways contributing to mucosal atrophy without acute inflammatory changes or intestinal epithelial cell (IEC) destruction seen in other intestinal injury/inflammation models. The removal of enteral nutrition is associated with decreased crypt proliferation, increased IEC apoptosis, a loss of epithelial barrier function (EBF), and altered enteric microbiota, resulting in a mild proinflammatory state and mucosal atrophy (1). Previous studies have shown that upregulation of tumor...

Homeostasis alteration within small intestinal mucosa after acute enteral refeeding in total parenteral nutrition mouse model

“…It is likely that the increased proinflammatory expression of TNF-␣ may have prevented the TPN-associated increase in IEC apoptosis, since this is very tightly linked to the TPN-associated IEC apoptosis (14). We have previously shown a critical link to this proinflammatory response and a loss of EBF (15,16). Thus, it is quite possible that the persistent loss of EBF in the refeeding group was due to the increase in the expression of this proinflammatory response.…”

Role of ADAM10 in intestinal crypt homeostasis and tumorigenesis

“…These results also highlight that no other ADAM can compensate for ADAM10 loss required for Notch signaling in development and normal adult crypt homeostasis [56]. For example, no Notch phenotype is observed in the ADAM17-deficient intestine[71]. …”

“…While activating mutations of the NOTCH-1 NRR that result in ligand-independent proteolysis are found frequently in human leukemia, illustrating the importance for tight control of metalloprotease access to the S2 site[70], it is currently unclear whether such ligand-independent Notch activation plays a role in mammalian development and normal tissue homeostasis. Indeed, as will be discussed later, the ADAM17-deficient intestine has no overt intestinal phenotype under normal physiological conditions[71]. …”

ADAM Proteases and Gastrointestinal Function

“…A slight increase in proinflammatory cytokine expression has been observed in the colonic mucosa of Adam17 ex/ex mice, which suggests sensitization to inflammatory stimuli (79, 80). Similarly, IEC-Adam17 KO mice on a C57BL/6J background do not have an intestinal phenotype (81, 82) (Table 2). No defects in the development and number of Peyer’s patches, in small intestinal barrier function, or in cytokine gene signatures have been observed (81, 82).…”

“…Similarly, IEC-Adam17 KO mice on a C57BL/6J background do not have an intestinal phenotype (81, 82) (Table 2). No defects in the development and number of Peyer’s patches, in small intestinal barrier function, or in cytokine gene signatures have been observed (81, 82). The normal intestinal secretory differentiation in hypomorphic Adam17 mice and IEC-Adam17 KO mice indicates that ADAM17 is not required for Notch signaling in the crypt compartment (50).…”