Deficiency of Protein Tyrosine Phosphatase Non-Receptor Type 2 in Intestinal Epithelial Cells Has No Appreciable Impact on Dextran Sulphate Sodium Colitis Severity But Promotes Wound Healing

Abstract

Background/Aims: The protein tyrosine phosphatase non-receptor type 2 (PTPN2) is known to mediate susceptibility to inflammatory bowel diseases. Cell culture experiments suggest that PTPN2 influences barrier function, autophagy and secretion of pro-inflammatory cytokines. PTPN2 knockout mice die a few weeks after birth due to systemic inflammation, emphasizing the importance of this phosphatase in inflammatory processes. The aim of this study was to investigate the role of PTPN2 in colon epithelial cells by performing dextran sulphate sodium (DSS)-induced colitis in PTPN2xVilCre mice. Methods: Acute colitis was induced by administering 2.5 or 2% DSS for 7 days and chronic colitis by 4 cycles of treatment using 1% DSS. Body weight of mice was measured regularly and colonoscopy was done at the end of the experiments. Mice were sacrificed afterwards and colon specimens were obtained for H&E staining. For analysis of wound healing, mechanical wounds were introduced during endoscopy and wound closure assessed by daily colonoscopy. Results: Although colonoscopy and weight development suggested changes in colitis severity, the lack of any influence of PTPN2 deficiency on histological scoring for inflammation severity after acute or chronic DSS colitis indicates that colitis severity is not influenced by epithelial-specific loss of PTPN2. Chronic colitis induced the development of aberrant crypt foci more frequently in PTPN2xVilCre mice compared to their wild type littermates. On the other hand, loss of PTPN2-induced enhanced epithelial cell proliferation and promoted wound closure. Conclusions: Loss of PTPN2 in intestinal epithelial cells (IECs) has no significant influence on inflammation in DSS colitis. Obviously, loss of PTPN2 in IECs can be compensated in vivo, thereby suppressing a phenotype. This lack of a colitis-phenotype might be due to enhanced epithelial cell proliferation and subsequent increased wound-healing capacity of the epithelial layer.

Deletion of Protein Tyrosine Phosphatase Nonreceptor Type 2 in Intestinal Epithelial Cells Results in Upregulation of the Related Phosphatase Protein Tyrosine Phosphatase Nonreceptor Type 23

“…The mice had either been left untreated or treated with 2% DSS in the drinking water for 7 days to induce an acute colitis [17]. As already described in Kasper et al [17], this treatment resulted in similar intestinal inflammation in wt and PTPN2-VilCre mice.…”

“…HT-29 cells were obtained from DSMZ (Braunschweig, Germany) and cultured as described previously [17] in culture medium (DMEM; Thermo Fisher Scientific, Waltham, MA, USA), supplemented with 1% nonessential amino acids (Thermo Fisher Scientific) and 10% FCS. For experiments, 1 × 10 6 cells were seeded in 12-well plates.…”

“…C57/Bl6 mice with a floxed PTPN2 gene (PTPN2 fl/fl mice, termed wild-type throughout the manuscript) and PTPN2 fl/fl mice expressing Cre-recombinase under the Villin promoter (PTPN2xVilCre mice) that lack PTPN2 specifically in IECs [17] were used for all studies. Acute colitis was induced via administration of 2.5% DSS in the drinking water as described by Kasper et al [17].…”

“…Acute colitis was induced via administration of 2.5% DSS in the drinking water as described by Kasper et al [17]. To induce colitis-associated tumors, mice were treated for 3 consecutive cycles consisting of 7 days with 1.5% DSS followed by 10 days recovery phase each.…”

“…These in vitro findings suggest that PTPN2 is important for the preservation of intestinal barrier functions, especially upon inflammatory insults. However, in vivo experiments from Kasper et al [17] showed that mice that specifically lack PTPN2 in IECs do not show enhanced disease severity upon induction of acute or chronic dextran sulfate sodium (DSS)-mediated colitis. Of note, those mice exhibit increased IEC proliferation and faster intestinal wound healing.…”