title: The Cytosolic Microbial Receptor Nod2 Regulates Small Intestinal Crypt Damage and Epithelial Regeneration following T Cell-Induced Enteropathy.
abstract: Loss of function in the NOD2 gene is associated with a higher risk of developing Crohn's disease (CD). CD is characterized by activation of T cells and activated T cells are involved in mucosal inflammation and mucosal damage. We found that acute T cell activation with anti-CD3 mAb induced stronger small intestinal mucosal damage in NOD2(-/-) mice compared with wild-type mice. This enhanced mucosal damage was characterized by loss of crypt architecture, increased epithelial cell apoptosis, delayed epithelial regeneration and an accumulation of inflammatory cytokines and Th17 cells in the small intestine. Partial microbiota depletion with antibiotics did not decrease mucosal damage 1 d after anti-CD3 mAb injection, but it significantly reduced crypt damage and inflammatory cytokine secretion in NOD2(-/-) mice 3 d after anti-CD3 mAb injection, indicating that microbial sensing by Nod2 was important to control mucosal damage and epithelial regeneration after anti-CD3 mAb injection. To determine which cells play a key role in microbial sensing and regulation of mucosal damage, we engineered mice carrying a cell-specific deletion of Nod2 in villin and Lyz2-expressing cells. T cell activation did not worsen crypt damage in mice carrying either cell-specific deletion of Nod2 compared with wild-type mice. However, increased numbers of apoptotic epithelial cells and higher expression of TNF-α and IL-22 were observed in mice carrying a deletion of Nod2 in Lyz2-expressing cells. Taken together, our results demonstrate that microbial sensing by Nod2 is an important mechanism to regulate small intestinal mucosal damage following acute T cell activation.
authors.affiliation: Department of Medicine, University of Toronto, Toronto, Ontario M5S 1A8, Canada;
authors.forename: Galliano
authors.initials: G
authors.lastname: Zanello
authors.affiliation: Department of Immunology, University of Toronto, Toronto, Ontario M5S 1A8, Canada;
authors.forename: Ashleigh
authors.identifier: 0000-0002-0856-2759
authors.initials: A
authors.lastname: Goethel
authors.affiliation: Department of Medicine, University of Toronto, Toronto, Ontario M5S 1A8, Canada;
authors.forename: Sandrine
authors.identifier: 0000-0002-1508-0934
authors.initials: S
authors.lastname: Rouquier
authors.affiliation: Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada;
authors.forename: David
authors.identifier: 0000-0002-9798-9526
authors.initials: D
authors.lastname: Prescott
authors.affiliation: Department of Immunology, University of Toronto, Toronto, Ontario M5S 1A8, Canada;
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Robertson
authors.affiliation: Department of Immunology, University of Toronto, Toronto, Ontario M5S 1A8, Canada;
authors.forename: Charles
authors.initials: C
authors.lastname: Maisonneuve
authors.affiliation: Department of Pathology and Laboratory Medicine, St. Michael's Hospital, Toronto, Ontario M5B 1W8, Canada;
authors.forename: Catherine
authors.initials: C
authors.lastname: Streutker
authors.affiliation: Department of Immunology, University of Toronto, Toronto, Ontario M5S 1A8, Canada;
authors.forename: Dana J
authors.initials: DJ
authors.lastname: Philpott
authors.affiliation: Department of Medicine, University of Toronto, Toronto, Ontario M5S 1A8, Canada; Department of Immunology, University of Toronto, Toronto, Ontario M5S 1A8, Canada; Zane Cohen Centre for Digestive Diseases, The Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario M5G 1X5, Canada; and Division of Gastroenterology, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada KCroitoru@mtsinai.on.ca.
authors.forename: Kenneth
authors.identifier: 0000-0003-1231-0180
authors.initials: K
authors.lastname: Croitoru
mesh_terms: D000818:Animals; D017209:Apoptosis; D002478:Cells, Cultured; D003424:Crohn Disease / Q000235:genetics*; D003600:Cytosol / Q000378:metabolism; D006801:Humans; D007378:Interleukins / Q000378:metabolism; D007413:Intestinal Mucosa / Q000276:immunology* / Q000473:pathology; D007421:Intestine, Small / Q000473:pathology*; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics / Q000378:metabolism*; D012038:Regeneration; D013601:T-Lymphocytes / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D000097043:Interleukin-22
chemical_list: D007378:Interleukins; D053473:Nod2 Signaling Adaptor Protein; D014409:Tumor Necrosis Factor-alpha; D000097043:Interleukin-22