title: Loss of T-cell protein tyrosine phosphatase in the intestinal epithelium promotes local inflammation by increasing colonic stem cell proliferation.
abstract: T-cell protein tyrosine phosphatase (TC-PTP) has a critical role in the development of the immune system and has been identified as a negative regulator of inflammation. Single-nucleotide polymorphisms in the TC-PTP locus have been associated with increased susceptibility to inflammatory bowel diseases (IBDs) in patients. To further understand how TC-PTP is related to IBDs, we investigated the role of TC-PTP in maintaining the intestinal epithelial barrier using an in vivo genetic approach. Intestinal epithelial cell (IEC)-specific deletion of TC-PTP was achieved in a mouse model at steady state and in the context of dextran sulphate sodium (DSS)-induced colitis. Knockout (KO) of TC-PTP in IECs did not result in an altered intestinal barrier. However, upon DSS treatment, IEC-specific TC-PTP KO mice displayed a more severe colitis phenotype with a corresponding increase in the immune response and inflammatory cytokine profile. The absence of TC-PTP caused an altered turnover of IECs, which is further explained by the role of the tyrosine phosphatase in colonic stem cell (CoSC) proliferation. Our results suggest a novel role for TC-PTP in regulating the homeostasis of CoSC proliferation. This supports the protective function of TC-PTP against IBDs, independently of its previously demonstrated role in intestinal immunity.
authors.affiliation: Department of Biochemistry, McGill University, Montréal, Québec, Canada.|Rosalind and Morris Goodman Cancer Research Centre, Montréal, Québec, Canada.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Bussières-Marmen
authors.affiliation: Department of Biochemistry, McGill University, Montréal, Québec, Canada.|Rosalind and Morris Goodman Cancer Research Centre, Montréal, Québec, Canada.
authors.forename: Valérie
authors.initials: V
authors.lastname: Vinette
authors.affiliation: Department of Microbiology and Immunology, McGill University, Montréal, Québec, Canada.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Gungabeesoon
authors.affiliation: Rosalind and Morris Goodman Cancer Research Centre, Montréal, Québec, Canada.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Aubry
authors.affiliation: Department of Biochemistry, McGill University, Montréal, Québec, Canada.|Rosalind and Morris Goodman Cancer Research Centre, Montréal, Québec, Canada.
authors.forename: Luis Alberto
authors.initials: LA
authors.lastname: Pérez-Quintero
authors.affiliation: Department of Biochemistry, McGill University, Montréal, Québec, Canada. michel.tremblay@mcgill.ca.|Rosalind and Morris Goodman Cancer Research Centre, Montréal, Québec, Canada. michel.tremblay@mcgill.ca.|Department of Microbiology and Immunology, McGill University, Montréal, Québec, Canada. michel.tremblay@mcgill.ca.
authors.forename: Michel L
authors.initials: ML
authors.lastname: Tremblay
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D003092:Colitis / Q000139:chemically induced / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D003106:Colon / Q000473:pathology*; D016207:Cytokines / Q000378:metabolism; D016264:Dextran Sulfate; D004198:Disease Susceptibility; D020895:Enterocytes / Q000378:metabolism; D006706:Homeostasis; D007249:Inflammation / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D007413:Intestinal Mucosa / Q000201:enzymology* / Q000473:pathology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000378:metabolism; D054578:Protein Tyrosine Phosphatase, Non-Receptor Type 2 / Q000378:metabolism*; D013234:Stem Cells / Q000201:enzymology*
chemical_list: D016207:Cytokines; D016264:Dextran Sulfate; D054578:Protein Tyrosine Phosphatase, Non-Receptor Type 2
keywords: Colonic stem cells; DSS-induced colitis; TC-PTP; intestinal epithelial barrier