Expression of HMGCS2 in intestinal epithelial cells is downregulated in inflammatory bowel disease associated with endoplasmic reticulum stress
IntroductionThe Unfolded Protein Response, a mechanism triggered by the cell in response to Endoplasmic reticulum stress, is linked to inflammatory responses. Our aim was to identify novel Unfolded Protein Response-mechanisms that might be involved in triggering or perpetuating the inflammatory resp...
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Frontiers Media S.A.
2023-06-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1185517/full |
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| author | Beatriz Martín-Adrados Stefanie K. Wculek Sergio Fernández-Bravo Raúl Torres-Ruiz Raúl Torres-Ruiz Ana Valle-Noguera Maria José Gomez-Sánchez José Carlos Hernández-Walias Frederico Moraes Ferreira Ana María Corraliza David Sancho Vanesa Esteban Sandra Rodriguez-Perales Aránzazu Cruz-Adalia Helder I. Nakaya Azucena Salas David Bernardo David Bernardo David Bernardo Yolanda Campos-Martín Elena Martínez-Zamorano Diego Muñoz-López Manuel Gómez del Moral Francisco Javier Cubero Francisco Javier Cubero Richard S. Blumberg Eduardo Martínez-Naves |
| author_facet | Beatriz Martín-Adrados Stefanie K. Wculek Sergio Fernández-Bravo Raúl Torres-Ruiz Raúl Torres-Ruiz Ana Valle-Noguera Maria José Gomez-Sánchez José Carlos Hernández-Walias Frederico Moraes Ferreira Ana María Corraliza David Sancho Vanesa Esteban Sandra Rodriguez-Perales Aránzazu Cruz-Adalia Helder I. Nakaya Azucena Salas David Bernardo David Bernardo David Bernardo Yolanda Campos-Martín Elena Martínez-Zamorano Diego Muñoz-López Manuel Gómez del Moral Francisco Javier Cubero Francisco Javier Cubero Richard S. Blumberg Eduardo Martínez-Naves |
| author_sort | Beatriz Martín-Adrados |
| collection | DOAJ |
| description | IntroductionThe Unfolded Protein Response, a mechanism triggered by the cell in response to Endoplasmic reticulum stress, is linked to inflammatory responses. Our aim was to identify novel Unfolded Protein Response-mechanisms that might be involved in triggering or perpetuating the inflammatory response carried out by the Intestinal Epithelial Cells in the context of Inflammatory Bowel Disease.MethodsWe analyzed the transcriptional profile of human Intestinal Epithelial Cell lines treated with an Endoplasmic Reticulum stress inducer (thapsigargin) and/or proinflammatory stimuli. Several genes were further analyzed in colonic biopsies from Ulcerative Colitis patients and healthy controls. Lastly, we generated Caco-2 cells lacking HMGCS2 by CRISPR Cas-9 and analyzed the functional implications of its absence in Intestinal Epithelial Cells.ResultsExposure to a TLR ligand after thapsigargin treatment resulted in a powerful synergistic modulation of gene expression, which led us to identify new genes and pathways that could be involved in inflammatory responses linked to the Unfolded Protein Response. Key differentially expressed genes in the array also exhibited transcriptional alterations in colonic biopsies from active Ulcerative Colitis patients, including NKG2D ligands and the enzyme HMGCS2. Moreover, functional studies showed altered metabolic responses and epithelial barrier integrity in HMGCS2 deficient cell lines.ConclusionWe have identified new genes and pathways that are regulated by the Unfolded Protein Response in the context of Inflammatory Bowel Disease including HMGCS2, a gene involved in the metabolism of Short Chain Fatty Acids that may have an important role in intestinal inflammation linked to Endoplasmic Reticulum stress and the resolution of the epithelial damage. |
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| language | English |
| last_indexed | 2024-03-13T02:14:55Z |
| publishDate | 2023-06-01 |
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| spelling | doaj.art-59dfd819e60246a9be340bee3f602a6e2023-06-30T16:20:29ZengFrontiers Media S.A.Frontiers in Immunology1664-32242023-06-011410.3389/fimmu.2023.11855171185517Expression of HMGCS2 in intestinal epithelial cells is downregulated in inflammatory bowel disease associated with endoplasmic reticulum stressBeatriz Martín-Adrados0Stefanie K. Wculek1Sergio Fernández-Bravo2Raúl Torres-Ruiz3Raúl Torres-Ruiz4Ana Valle-Noguera5Maria José Gomez-Sánchez6José Carlos Hernández-Walias7Frederico Moraes Ferreira8Ana María Corraliza9David Sancho10Vanesa Esteban11Sandra Rodriguez-Perales12Aránzazu Cruz-Adalia13Helder I. Nakaya14Azucena Salas15David Bernardo16David Bernardo17David Bernardo18Yolanda Campos-Martín19Elena Martínez-Zamorano20Diego Muñoz-López21Manuel Gómez del Moral22Francisco Javier Cubero23Francisco Javier Cubero24Richard S. Blumberg25Eduardo Martínez-Naves26Department of Immunology, Ophthalmology and ORL, School of Medicine, Universidad Complutense of Madrid (UCM), Instituto de Investigación Sanitaria Hospital 12 de octubre (imas12), Madrid, SpainImmunobiology Laboratory, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, SpainDepartment of Allergy and Immunology, IIS-Fundación Jiménez Díaz, Universidad Autónoma of Madrid, Madrid, SpainMolecular Cytogenetics & Genome Editing Unit, Human Cancer Genetics Program, Centro Nacional de Investigaciones Oncológicas (CNIO), Melchor Fernández Almagro, Madrid, SpainCentro de Investigaciones Energéticas Medioambientales y Tecnológicas (CIEMAT), Advanced Therapies Unit, Hematopoietic Innovative Therapies Division, Instituto de Investigación Sanitaria Fundación Jiménez Díaz, Universidad Autónoma de Madrid (IIS-FJD, UAM), Madrid, SpainDepartment of Immunology, Ophthalmology and ORL, School of Medicine, Universidad Complutense of Madrid (UCM), Instituto de Investigación Sanitaria Hospital 12 de octubre (imas12), Madrid, SpainDepartment of Immunology, Ophthalmology and ORL, School of Medicine, Universidad Complutense of Madrid (UCM), Instituto de Investigación Sanitaria Hospital 12 de octubre (imas12), Madrid, SpainDepartment of Immunology, Ophthalmology and ORL, School of Medicine, Universidad Complutense of Madrid (UCM), Instituto de Investigación Sanitaria Hospital 12 de octubre (imas12), Madrid, SpainLIM50, Division of Pathology, University of São Paulo School of Medicine, São Paulo, SP, BrazilDepartment of Gastroenterology, Instituto de Investigaciones Biomédicas August Pi i Sunyer (IDIBAPS), Hospital Clinic of Barcelona, Centro de Investigación Biomédica en Red-Enfermedades Hepáticas y Digestivas (CIBER-EHD), Barcelona, SpainImmunobiology Laboratory, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, SpainDepartment of Allergy and Immunology, IIS-Fundación Jiménez Díaz, Universidad Autónoma of Madrid, Madrid, SpainMolecular Cytogenetics & Genome Editing Unit, Human Cancer Genetics Program, Centro Nacional de Investigaciones Oncológicas (CNIO), Melchor Fernández Almagro, Madrid, SpainDepartment of Immunology, Ophthalmology and ORL, School of Medicine, Universidad Complutense of Madrid (UCM), Instituto de Investigación Sanitaria Hospital 12 de octubre (imas12), Madrid, SpainDepartment of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences, University of São Paulo (USP), Hospital Israelita Albert Einstein, São Paulo, SP, BrazilDepartment of Gastroenterology, Instituto de Investigaciones Biomédicas August Pi i Sunyer (IDIBAPS), Hospital Clinic of Barcelona, Centro de Investigación Biomédica en Red-Enfermedades Hepáticas y Digestivas (CIBER-EHD), Barcelona, SpainGut Immunology Research Group, Instituto de Investigación del Hospital Universitario de la Princesa, Madrid, Spain0Unidad de Excelencia Instituto de Biología y Genética Molecular (IBGM, Universidad de Valladolid-Consejo Superior de Investigaciones Científicas (CSIC)), Valladolid, Spain1Centro de Investigaciones Biomédicas en Red de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, Madrid, Spain2Department of Pathology, Hospital Universitario de Toledo, Toledo, Spain2Department of Pathology, Hospital Universitario de Toledo, Toledo, Spain2Department of Pathology, Hospital Universitario de Toledo, Toledo, Spain3Department of Cellular Biology, School of Medicine, Universidad Complutense of Madrid (UCM), Madrid, SpainDepartment of Immunology, Ophthalmology and ORL, School of Medicine, Universidad Complutense of Madrid (UCM), Instituto de Investigación Sanitaria Hospital 12 de octubre (imas12), Madrid, Spain4Centro de Investigaciones Biomédicas en Red de Enfermeddes Hepáticas y Digestivas (CIBEREHD), Barcelona, Spain5Division of Gastroenterology, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United StatesDepartment of Immunology, Ophthalmology and ORL, School of Medicine, Universidad Complutense of Madrid (UCM), Instituto de Investigación Sanitaria Hospital 12 de octubre (imas12), Madrid, SpainIntroductionThe Unfolded Protein Response, a mechanism triggered by the cell in response to Endoplasmic reticulum stress, is linked to inflammatory responses. Our aim was to identify novel Unfolded Protein Response-mechanisms that might be involved in triggering or perpetuating the inflammatory response carried out by the Intestinal Epithelial Cells in the context of Inflammatory Bowel Disease.MethodsWe analyzed the transcriptional profile of human Intestinal Epithelial Cell lines treated with an Endoplasmic Reticulum stress inducer (thapsigargin) and/or proinflammatory stimuli. Several genes were further analyzed in colonic biopsies from Ulcerative Colitis patients and healthy controls. Lastly, we generated Caco-2 cells lacking HMGCS2 by CRISPR Cas-9 and analyzed the functional implications of its absence in Intestinal Epithelial Cells.ResultsExposure to a TLR ligand after thapsigargin treatment resulted in a powerful synergistic modulation of gene expression, which led us to identify new genes and pathways that could be involved in inflammatory responses linked to the Unfolded Protein Response. Key differentially expressed genes in the array also exhibited transcriptional alterations in colonic biopsies from active Ulcerative Colitis patients, including NKG2D ligands and the enzyme HMGCS2. Moreover, functional studies showed altered metabolic responses and epithelial barrier integrity in HMGCS2 deficient cell lines.ConclusionWe have identified new genes and pathways that are regulated by the Unfolded Protein Response in the context of Inflammatory Bowel Disease including HMGCS2, a gene involved in the metabolism of Short Chain Fatty Acids that may have an important role in intestinal inflammation linked to Endoplasmic Reticulum stress and the resolution of the epithelial damage.https://www.frontiersin.org/articles/10.3389/fimmu.2023.1185517/fullinflammatory bowel diseaseinflammationER stressHMGCS2unfolded protein response (UPR) |
| spellingShingle | Beatriz Martín-Adrados Stefanie K. Wculek Sergio Fernández-Bravo Raúl Torres-Ruiz Raúl Torres-Ruiz Ana Valle-Noguera Maria José Gomez-Sánchez José Carlos Hernández-Walias Frederico Moraes Ferreira Ana María Corraliza David Sancho Vanesa Esteban Sandra Rodriguez-Perales Aránzazu Cruz-Adalia Helder I. Nakaya Azucena Salas David Bernardo David Bernardo David Bernardo Yolanda Campos-Martín Elena Martínez-Zamorano Diego Muñoz-López Manuel Gómez del Moral Francisco Javier Cubero Francisco Javier Cubero Richard S. Blumberg Eduardo Martínez-Naves Expression of HMGCS2 in intestinal epithelial cells is downregulated in inflammatory bowel disease associated with endoplasmic reticulum stress Frontiers in Immunology inflammatory bowel disease inflammation ER stress HMGCS2 unfolded protein response (UPR) |
| title | Expression of HMGCS2 in intestinal epithelial cells is downregulated in inflammatory bowel disease associated with endoplasmic reticulum stress |
| title_full | Expression of HMGCS2 in intestinal epithelial cells is downregulated in inflammatory bowel disease associated with endoplasmic reticulum stress |
| title_fullStr | Expression of HMGCS2 in intestinal epithelial cells is downregulated in inflammatory bowel disease associated with endoplasmic reticulum stress |
| title_full_unstemmed | Expression of HMGCS2 in intestinal epithelial cells is downregulated in inflammatory bowel disease associated with endoplasmic reticulum stress |
| title_short | Expression of HMGCS2 in intestinal epithelial cells is downregulated in inflammatory bowel disease associated with endoplasmic reticulum stress |
| title_sort | expression of hmgcs2 in intestinal epithelial cells is downregulated in inflammatory bowel disease associated with endoplasmic reticulum stress |
| topic | inflammatory bowel disease inflammation ER stress HMGCS2 unfolded protein response (UPR) |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1185517/full |
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