PTPN2 Is a Critical Regulator of Ileal Paneth Cell Viability and Function in MiceSummary
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 microbi...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-01-01
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| Series: | Cellular and Molecular Gastroenterology and Hepatology |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352345X23000498 |
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| author | Vinicius Canale Marianne R. Spalinger Rocio Alvarez Anica Sayoc-Becerra Golshid Sanati Salomon Manz Pritha Chatterjee Alina N. Santos Hillmin Lei Sharon Jahng Timothy Chu Ali Shawki Elaine Hanson Lars Eckmann André J. Ouellette Declan F. McCole |
| author_facet | Vinicius Canale Marianne R. Spalinger Rocio Alvarez Anica Sayoc-Becerra Golshid Sanati Salomon Manz Pritha Chatterjee Alina N. Santos Hillmin Lei Sharon Jahng Timothy Chu Ali Shawki Elaine Hanson Lars Eckmann André J. Ouellette Declan F. McCole |
| author_sort | Vinicius Canale |
| collection | DOAJ |
| 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 Ptpn2ΔIEC mice, which also showed impaired lysozyme protein levels in Paneth cells compared with Ptpn2fl/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. |
| first_indexed | 2024-03-13T10:21:48Z |
| format | Article |
| id | doaj.art-6312182efc1f47dca7056b2a59fb791d |
| institution | Directory Open Access Journal |
| issn | 2352-345X |
| language | English |
| last_indexed | 2024-03-13T10:21:48Z |
| publishDate | 2023-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cellular and Molecular Gastroenterology and Hepatology |
| spelling | doaj.art-6312182efc1f47dca7056b2a59fb791d2023-05-20T04:30:16ZengElsevierCellular and Molecular Gastroenterology and Hepatology2352-345X2023-01-011613962PTPN2 Is a Critical Regulator of Ileal Paneth Cell Viability and Function in MiceSummaryVinicius Canale0Marianne R. Spalinger1Rocio Alvarez2Anica Sayoc-Becerra3Golshid Sanati4Salomon Manz5Pritha Chatterjee6Alina N. Santos7Hillmin Lei8Sharon Jahng9Timothy Chu10Ali Shawki11Elaine Hanson12Lars Eckmann13André J. Ouellette14Declan F. McCole15Division of Biomedical Sciences, University of California Riverside, Riverside, California; Biochemistry and Molecular Biology Department, University of California Riverside, Riverside, California; CAPES Foundation, Ministry of Education of Brazil, Brasília, BrazilDivision of Biomedical Sciences, University of California Riverside, Riverside, California; Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, SwitzerlandDivision of Biomedical Sciences, University of California Riverside, Riverside, CaliforniaDivision of Biomedical Sciences, University of California Riverside, Riverside, CaliforniaDivision of Biomedical Sciences, University of California Riverside, Riverside, CaliforniaDivision of Biomedical Sciences, University of California Riverside, Riverside, California; Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, SwitzerlandDivision of Biomedical Sciences, University of California Riverside, Riverside, California; Biochemistry and Molecular Biology Department, University of California Riverside, Riverside, CaliforniaDivision of Biomedical Sciences, University of California Riverside, Riverside, CaliforniaDivision of Biomedical Sciences, University of California Riverside, Riverside, CaliforniaDivision of Biomedical Sciences, University of California Riverside, Riverside, CaliforniaDivision of Biomedical Sciences, University of California Riverside, Riverside, CaliforniaDivision of Biomedical Sciences, University of California Riverside, Riverside, CaliforniaDivision of Gastroenterology, University of California, San Diego, La Jolla, CaliforniaDivision of Gastroenterology, University of California, San Diego, La Jolla, CaliforniaDepartment of Pathology and Laboratory Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CaliforniaDivision of Biomedical Sciences, University of California Riverside, Riverside, California; Correspondence Address correspondence to: Declan F. McCole, PhD, 307 School of Medicine Research Building, University of California, 900 University Avenue, Riverside, California 92521.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 Ptpn2ΔIEC mice, which also showed impaired lysozyme protein levels in Paneth cells compared with Ptpn2fl/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.http://www.sciencedirect.com/science/article/pii/S2352345X23000498Antimicrobial PeptidesTCPTPLysozymeIntestinal Epithelial CellsInflammatory Bowel DiseaseMicrobiome |
| spellingShingle | Vinicius Canale Marianne R. Spalinger Rocio Alvarez Anica Sayoc-Becerra Golshid Sanati Salomon Manz Pritha Chatterjee Alina N. Santos Hillmin Lei Sharon Jahng Timothy Chu Ali Shawki Elaine Hanson Lars Eckmann André J. Ouellette Declan F. McCole PTPN2 Is a Critical Regulator of Ileal Paneth Cell Viability and Function in MiceSummary Cellular and Molecular Gastroenterology and Hepatology Antimicrobial Peptides TCPTP Lysozyme Intestinal Epithelial Cells Inflammatory Bowel Disease Microbiome |
| title | PTPN2 Is a Critical Regulator of Ileal Paneth Cell Viability and Function in MiceSummary |
| title_full | PTPN2 Is a Critical Regulator of Ileal Paneth Cell Viability and Function in MiceSummary |
| title_fullStr | PTPN2 Is a Critical Regulator of Ileal Paneth Cell Viability and Function in MiceSummary |
| title_full_unstemmed | PTPN2 Is a Critical Regulator of Ileal Paneth Cell Viability and Function in MiceSummary |
| title_short | PTPN2 Is a Critical Regulator of Ileal Paneth Cell Viability and Function in MiceSummary |
| title_sort | ptpn2 is a critical regulator of ileal paneth cell viability and function in micesummary |
| topic | Antimicrobial Peptides TCPTP Lysozyme Intestinal Epithelial Cells Inflammatory Bowel Disease Microbiome |
| url | http://www.sciencedirect.com/science/article/pii/S2352345X23000498 |
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