دورية أكاديمية
Expression of Free Fatty Acid Receptor 2 by Dendritic Cells Prevents Their Expression of Interleukin 27 and Is Required for Maintenance of Mucosal Barrier and Immune Response Against Colorectal Tumors in Mice.
| العنوان: | Expression of Free Fatty Acid Receptor 2 by Dendritic Cells Prevents Their Expression of Interleukin 27 and Is Required for Maintenance of Mucosal Barrier and Immune Response Against Colorectal Tumors in Mice. |
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| المؤلفون: | Lavoie S; Departments of Immunology and Infectious Diseases and Genetics and Complex Diseases, Harvard T. H. Chan School of Public Health, Boston, Massachusetts., Chun E; Departments of Immunology and Infectious Diseases and Genetics and Complex Diseases, Harvard T. H. Chan School of Public Health, Boston, Massachusetts., Bae S; Departments of Immunology and Infectious Diseases and Genetics and Complex Diseases, Harvard T. H. Chan School of Public Health, Boston, Massachusetts., Brennan CA; Departments of Immunology and Infectious Diseases and Genetics and Complex Diseases, Harvard T. H. Chan School of Public Health, Boston, Massachusetts., Gallini Comeau CA; Departments of Immunology and Infectious Diseases and Genetics and Complex Diseases, Harvard T. H. Chan School of Public Health, Boston, Massachusetts., Lang JK; Departments of Immunology and Infectious Diseases and Genetics and Complex Diseases, Harvard T. H. Chan School of Public Health, Boston, Massachusetts., Michaud M; Departments of Immunology and Infectious Diseases and Genetics and Complex Diseases, Harvard T. H. Chan School of Public Health, Boston, Massachusetts., Hoveyda HR; Euroscreen SA, Gosselies, Belgium., Fraser GL; EPICS SA, Gosselies, Belgium., Fuller MH; Division of Endocrinology, Diabetes, and Metabolism, University of Illinois at Chicago, Chicago, Illinois., Layden BT; Division of Endocrinology, Diabetes, and Metabolism, University of Illinois at Chicago, Chicago, Illinois; Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois., Glickman JN; Department of Pathology, Harvard Medical School, Boston, Massachusetts; Beth Israel Deaconess Medical Center, Boston, Massachusetts., Garrett WS; Departments of Immunology and Infectious Diseases and Genetics and Complex Diseases, Harvard T. H. Chan School of Public Health, Boston, Massachusetts; Broad Institute of Harvard and MIT, Cambridge, Massachusetts; Department and Division of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts. Electronic address: wgarrett@hsph.harvard.edu. |
| المصدر: | Gastroenterology [Gastroenterology] 2020 Apr; Vol. 158 (5), pp. 1359-1372.e9. Date of Electronic Publication: 2020 Jan 07. |
| نوع المنشور: | Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S. |
| اللغة: | English |
| بيانات الدورية: | Publisher: W.B. Saunders Country of Publication: United States NLM ID: 0374630 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1528-0012 (Electronic) Linking ISSN: 00165085 NLM ISO Abbreviation: Gastroenterology Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: Philadelphia, PA : W.B. Saunders Original Publication: Baltimore. |
| مواضيع طبية MeSH: | Colitis/*pathology , Colonic Neoplasms/*immunology , Dendritic Cells/*immunology , Gastrointestinal Microbiome/*immunology , Interleukins/*metabolism , Receptors, G-Protein-Coupled/*metabolism, Adenomatous Polyposis Coli Protein/genetics ; Animals ; CD8-Positive T-Lymphocytes/immunology ; CD8-Positive T-Lymphocytes/metabolism ; Carcinogenesis/drug effects ; Carcinogenesis/genetics ; Carcinogenesis/immunology ; Colitis/chemically induced ; Colitis/immunology ; Colon/drug effects ; Colon/microbiology ; Colon/pathology ; Colonic Neoplasms/genetics ; Colonic Neoplasms/pathology ; Dendritic Cells/metabolism ; Dextran Sulfate/toxicity ; Disease Models, Animal ; Disease Progression ; Fatty Acids, Nonesterified/metabolism ; Female ; Humans ; Interleukins/immunology ; Intestinal Mucosa/drug effects ; Intestinal Mucosa/microbiology ; Intestinal Mucosa/pathology ; Male ; Mice ; Mice, Knockout ; Permeability ; Primary Cell Culture ; Receptors, G-Protein-Coupled/agonists ; Receptors, G-Protein-Coupled/genetics |
| مستخلص: | Background & Aims: Intestinal microbes and their metabolites affect the development of colorectal cancer (CRC). Short-chain fatty acids are metabolites generated by intestinal microbes from dietary fiber. We investigated the mechanisms by which free fatty acid receptor 2 (FFAR2), a receptor for short-chain fatty acids that can affect the composition of the intestinal microbiome, contributes to the pathogenesis of CRC. Methods: We performed studies with Apc Min/+ mice, Apc Min/+ Ffar2 -/- mice, mice with conditional disruption of Ffar2 in dendritic cells (DCs) (Ffar2 fl/fl CD11c-Cre mice), Apc Min/+ Ffar2 fl/fl CD11c-Cre mice, and Ffar2 fl/fl mice (controls); some mice were given dextran sodium sulfate to induce colitis, with or without a FFAR2 agonist or an antibody against interleukin 27 (IL27). Colon and tumor tissues were analyzed by histology, quantitative polymerase chain reaction, and 16S ribosomal RNA gene sequencing; lamina propria and mesenteric lymph node tissues were analyzed by RNA sequencing and flow cytometry. Intestinal permeability was measured after gavage with fluorescently labeled dextran. We collected data on colorectal tumors from The Cancer Genome Atlas. Results: Apc Min/+ Ffar2 -/- mice developed significantly more spontaneous colon tumors than Apc Min/+ mice and had increased gut permeability before tumor development, associated with reduced expression of E-cadherin. Colon tumors from Apc Min/+ Ffar2 -/- mice had a higher number of bacteria than tumors from Apc Min/+ mice, as well as higher frequencies of CD39 + CD8 + T cells and exhausted or dying T cells. DCs from Apc Min/+ Ffar2 -/- mice had an altered state of activation, increased death, and higher production of IL27. Administration of an antibody against IL27 reduced the numbers of colon tumors in Apc Min/+ mice with colitis. Frequencies of CD39 + CD8 + T cells and IL27 + DCs were increased in colon lamina propria from Ffar2 fl/fl CD11c-Cre mice with colitis compared with control mice or mice without colitis. Apc Min/+ Ffar2 fl/fl CD11c-Cre mice developed even more tumors than Apc Min/+ Ffar2 fl/fl mice, and their tumors had even higher numbers of IL27 + DCs. Apc Min/+ mice with colitis given the FFAR2 agonist developed fewer colon tumors, with fewer IL27 + DCs, than mice not given the agonist. DCs incubated with the FFAR2 agonist no longer had gene expression patterns associated with activation or IL27 production. Conclusions: Loss of FFAR2 promotes colon tumorigenesis in mice by reducing gut barrier integrity, increasing tumor bacterial load, promoting exhaustion of CD8 + T cells, and overactivating DCs, leading to their death. Antibodies against IL27 and an FFAR2 agonist reduce tumorigenesis in mice and might be developed for the treatment of CRC. (Copyright © 2020 AGA Institute. Published by Elsevier Inc. All rights reserved.) |
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| معلومات مُعتمدة: | 27140 United Kingdom CRUK_ Cancer Research UK; F31 DK105653 United States DK NIDDK NIH HHS; R01 CA154426 United States CA NCI NIH HHS; P30 DK020595 United States DK NIDDK NIH HHS; T32 CA207021 United States CA NCI NIH HHS; C10674/A27140 United Kingdom CRUK_ Cancer Research UK; R01 DK104927 United States DK NIDDK NIH HHS; I01 BX003382 United States BX BLRD VA; R24 DK110499 United States DK NIDDK NIH HHS |
| فهرسة مساهمة: | Keywords: Cytokine: Cytotoxicity; Microbial Metabolite Receptor; SCFA |
| المشرفين على المادة: | 0 (Adenomatous Polyposis Coli Protein) 0 (Fatty Acids, Nonesterified) 0 (Ffar2 protein, mouse) 0 (Il27 protein, mouse) 0 (Interleukins) 0 (Receptors, G-Protein-Coupled) 0 (adenomatous polyposis coli protein, mouse) 9042-14-2 (Dextran Sulfate) |
| تواريخ الأحداث: | Date Created: 20200110 Date Completed: 20200710 Latest Revision: 20240210 |
| رمز التحديث: | 20240210 |
| مُعرف محوري في PubMed: | PMC7291292 |
| DOI: | 10.1053/j.gastro.2019.12.027 |
| PMID: | 31917258 |
| قاعدة البيانات: | MEDLINE |
Full Text via ClinicalKey 
Full Text Finder | تدمد: | 1528-0012 |
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| DOI: | 10.1053/j.gastro.2019.12.027 |