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PTPN2 Is a Critical Regulator of Ileal Paneth Cell Viability and Function in Mice
BACKGROUND & AIMS: Loss-of-function variants in the PTPN2 gene are associated with increased risk of inflammatory bowel disease. We recently showed that Ptpn2 is critical for intestinal epithelial cell (IEC) barrier maintenance, IEC–macrophage communication, and modulation of the gut microbiome...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10213106/ https://www.ncbi.nlm.nih.gov/pubmed/37030630 http://dx.doi.org/10.1016/j.jcmgh.2023.03.009 |
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author | Canale, Vinicius Spalinger, Marianne R. Alvarez, Rocio Sayoc-Becerra, Anica Sanati, Golshid Manz, Salomon Chatterjee, Pritha Santos, Alina N. Lei, Hillmin Jahng, Sharon Chu, Timothy Shawki, Ali Hanson, Elaine Eckmann, Lars Ouellette, André J. McCole, Declan F. |
author_facet | Canale, Vinicius Spalinger, Marianne R. Alvarez, Rocio Sayoc-Becerra, Anica Sanati, Golshid Manz, Salomon Chatterjee, Pritha Santos, Alina N. Lei, Hillmin Jahng, Sharon Chu, Timothy Shawki, Ali Hanson, Elaine Eckmann, Lars Ouellette, André J. McCole, Declan F. |
author_sort | Canale, Vinicius |
collection | PubMed |
description | BACKGROUND & AIMS: Loss-of-function variants in the PTPN2 gene are associated with increased risk of inflammatory bowel disease. We recently showed that Ptpn2 is critical for intestinal epithelial cell (IEC) barrier maintenance, IEC–macrophage communication, and modulation of the gut microbiome in mice, restricting expansion of a small intestinal pathobiont associated with inflammatory bowel disease. Here, we aimed to identify how Ptpn2 loss affects ileal IEC subtypes and their function in vivo. METHODS: Constitutive Ptpn2 wild-type, heterozygous, and knockout (KO) mice, as well as mice with inducible deletion of Ptpn2 in IECs, were used in the study. Investigation was performed using imaging techniques, flow cytometry, enteroid culture, and analysis of gene and protein levels of IEC markers. RESULTS: Partial transcriptome analysis showed that expression of Paneth cell–associated antimicrobial peptides Lyz1, Pla2g2a, and Defa6 was down-regulated markedly in Ptpn2-KO mice compared with wild-type and heterozygous. In parallel, Paneth cell numbers were reduced, their endoplasmic reticulum architecture was disrupted, and the endoplasmic reticulum stress protein, C/EBP-homologous protein (CHOP), was increased in Ptpn2-KO mice. Despite reduced Paneth cell number, flow cytometry showed increased expression of the Paneth cell–stimulatory cytokines interleukin 22 and interferon γ(+) in CD4(+) T cells isolated from Ptpn2-KO ileum. Key findings in constitutive Ptpn2-KO mice were confirmed in epithelium-specific Ptpn2(ΔIEC) mice, which also showed impaired lysozyme protein levels in Paneth cells compared with Ptpn2(fl/fl) control mice. CONCLUSIONS: Constitutive Ptpn2 deficiency affects Paneth cell viability and compromises Paneth cell–specific antimicrobial peptide production. The observed effects may contribute to the increased susceptibility to intestinal infection and dysbiosis in these mice. |
format | Online Article Text |
id | pubmed-10213106 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
spelling | pubmed-102131062023-05-27 PTPN2 Is a Critical Regulator of Ileal Paneth Cell Viability and Function in Mice Canale, Vinicius Spalinger, Marianne R. Alvarez, Rocio Sayoc-Becerra, Anica Sanati, Golshid Manz, Salomon Chatterjee, Pritha Santos, Alina N. Lei, Hillmin Jahng, Sharon Chu, Timothy Shawki, Ali Hanson, Elaine Eckmann, Lars Ouellette, André J. McCole, Declan F. Cell Mol Gastroenterol Hepatol Original Research BACKGROUND & AIMS: Loss-of-function variants in the PTPN2 gene are associated with increased risk of inflammatory bowel disease. We recently showed that Ptpn2 is critical for intestinal epithelial cell (IEC) barrier maintenance, IEC–macrophage communication, and modulation of the gut microbiome in mice, restricting expansion of a small intestinal pathobiont associated with inflammatory bowel disease. Here, we aimed to identify how Ptpn2 loss affects ileal IEC subtypes and their function in vivo. METHODS: Constitutive Ptpn2 wild-type, heterozygous, and knockout (KO) mice, as well as mice with inducible deletion of Ptpn2 in IECs, were used in the study. Investigation was performed using imaging techniques, flow cytometry, enteroid culture, and analysis of gene and protein levels of IEC markers. RESULTS: Partial transcriptome analysis showed that expression of Paneth cell–associated antimicrobial peptides Lyz1, Pla2g2a, and Defa6 was down-regulated markedly in Ptpn2-KO mice compared with wild-type and heterozygous. In parallel, Paneth cell numbers were reduced, their endoplasmic reticulum architecture was disrupted, and the endoplasmic reticulum stress protein, C/EBP-homologous protein (CHOP), was increased in Ptpn2-KO mice. Despite reduced Paneth cell number, flow cytometry showed increased expression of the Paneth cell–stimulatory cytokines interleukin 22 and interferon γ(+) in CD4(+) T cells isolated from Ptpn2-KO ileum. Key findings in constitutive Ptpn2-KO mice were confirmed in epithelium-specific Ptpn2(ΔIEC) mice, which also showed impaired lysozyme protein levels in Paneth cells compared with Ptpn2(fl/fl) control mice. CONCLUSIONS: Constitutive Ptpn2 deficiency affects Paneth cell viability and compromises Paneth cell–specific antimicrobial peptide production. The observed effects may contribute to the increased susceptibility to intestinal infection and dysbiosis in these mice. Elsevier 2023-04-07 /pmc/articles/PMC10213106/ /pubmed/37030630 http://dx.doi.org/10.1016/j.jcmgh.2023.03.009 Text en © 2023 The Authors https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Original Research Canale, Vinicius Spalinger, Marianne R. Alvarez, Rocio Sayoc-Becerra, Anica Sanati, Golshid Manz, Salomon Chatterjee, Pritha Santos, Alina N. Lei, Hillmin Jahng, Sharon Chu, Timothy Shawki, Ali Hanson, Elaine Eckmann, Lars Ouellette, André J. McCole, Declan F. PTPN2 Is a Critical Regulator of Ileal Paneth Cell Viability and Function in Mice |
title | PTPN2 Is a Critical Regulator of Ileal Paneth Cell Viability and Function in Mice |
title_full | PTPN2 Is a Critical Regulator of Ileal Paneth Cell Viability and Function in Mice |
title_fullStr | PTPN2 Is a Critical Regulator of Ileal Paneth Cell Viability and Function in Mice |
title_full_unstemmed | PTPN2 Is a Critical Regulator of Ileal Paneth Cell Viability and Function in Mice |
title_short | PTPN2 Is a Critical Regulator of Ileal Paneth Cell Viability and Function in Mice |
title_sort | ptpn2 is a critical regulator of ileal paneth cell viability and function in mice |
topic | Original Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10213106/ https://www.ncbi.nlm.nih.gov/pubmed/37030630 http://dx.doi.org/10.1016/j.jcmgh.2023.03.009 |
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