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 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-α) expression that ultimately produces mucosal atrophy. Upregulation of TNF-α 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-α 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-α/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-α signaling from IECs attenuates TPN-induced mucosal atrophy. Importantly, this response remains dependent on the maintenance of functional EGFR signaling in IECs. TNF-α blockade in wild-type mice receiving TPN confirmed that soluble TNF-α signaling is responsible for downregulation of EGFR signaling in IECs. These results demonstrate that ADAM17-mediated TNF-α signaling from IECs has a significant role in the development of the proinflammatory state and mucosal atrophy observed in TPN-treated mice.
Section of Pediatric Surgery, Department of Surgery, University of Michigan Medical School, Ann Arbor, Michigan, USA.
Yongjia
Y
Feng
Division of Gastroenterology, Department of Pediatrics, University of Michigan Medical School, Ann Arbor, Michigan, USA Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
Yu-Hwai
YH
Tsai
Section of Pediatric Surgery, Department of Surgery, University of Michigan Medical School, Ann Arbor, Michigan, USA.
Weidong
W
Xiao
Section of Pediatric Surgery, Department of Surgery, University of Michigan Medical School, Ann Arbor, Michigan, USA.
Matthew W
MW
Ralls
Division of Gastroenterology, Department of Pediatrics, University of Michigan Medical School, Ann Arbor, Michigan, USA.
Alex
A
Stoeck
Department of Pathology, University of Washington, Seattle, Washington, USA.
Carole L
CL
Wilson
Department of Pathology, University of Washington, Seattle, Washington, USA.
Elaine W
EW
Raines
Section of Pediatric Surgery, Department of Surgery, University of Michigan Medical School, Ann Arbor, Michigan, USA dttlbm@med.umich.edu peter.dempsey@ucdenver.edu.
Daniel H
DH
Teitelbaum
Division of Gastroenterology, Department of Pediatrics, University of Michigan Medical School, Ann Arbor, Michigan, USA Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan, USA Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, University of Colorado Medical School, Aurora, Colorado, USA dttlbm@med.umich.edu peter.dempsey@ucdenver.edu.
Peter J
PJ
Dempsey
D051722:ADAM Proteins / Q000235:genetics* / Q000276:immunology; D000072198:ADAM17 Protein; D000818:Animals; D017209:Apoptosis; D001284:Atrophy / Q000276:immunology / Q000473:pathology; D049109:Cell Proliferation; D016207:Cytokines / Q000276:immunology; D066246:ErbB Receptors / Q000276:immunology; D005260:Female; D055786:Gene Knockout Techniques; D006801:Humans; D007413:Intestinal Mucosa / Q000166:cytology / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010289:Parenteral Nutrition, Total / Q000009:adverse effects*; D050796:STAT3 Transcription Factor / Q000276:immunology; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology*
D016207:Cytokines; D050796:STAT3 Transcription Factor; D014409:Tumor Necrosis Factor-alpha; D066246:ErbB Receptors; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human; C000606463:Adam17 protein, mouse