Chromofungin Ameliorates the Progression of Colitis by Regulating Alternatively Activated Macrophages
Ulcerative colitis (UC) is characterized by a functional dysregulation of alternatively activated macrophage (AAM) and intestinal epithelial cells (IECs) homeostasis. Chromogranin-A (CHGA) secreted by neuroendocrine cells is implicated in intestinal inflammation and immune dysregulation. CHGA underg...
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| Format: | Article |
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Frontiers Media S.A.
2017-09-01
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| Series: | Frontiers in Immunology |
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| Online Access: | http://journal.frontiersin.org/article/10.3389/fimmu.2017.01131/full |
| _version_ | 1811318547309133824 |
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| author | Nour Eissa Nour Eissa Hayam Hussein Laëtitia Kermarrec Jasmine Grover Marie-Hélène Et Metz-Boutigue Charles N. Bernstein Charles N. Bernstein Jean-Eric Ghia Jean-Eric Ghia Jean-Eric Ghia Jean-Eric Ghia |
| author_facet | Nour Eissa Nour Eissa Hayam Hussein Laëtitia Kermarrec Jasmine Grover Marie-Hélène Et Metz-Boutigue Charles N. Bernstein Charles N. Bernstein Jean-Eric Ghia Jean-Eric Ghia Jean-Eric Ghia Jean-Eric Ghia |
| author_sort | Nour Eissa |
| collection | DOAJ |
| description | Ulcerative colitis (UC) is characterized by a functional dysregulation of alternatively activated macrophage (AAM) and intestinal epithelial cells (IECs) homeostasis. Chromogranin-A (CHGA) secreted by neuroendocrine cells is implicated in intestinal inflammation and immune dysregulation. CHGA undergoes proteolytic processing to generate CHGA-derived peptides. Chromofungin (CHR: CHGA47–66) is a short CHGA-derived peptide encoded by CHGA Exon-IV and is involved in innate immune regulation, but the basis is poorly investigated. We investigated the expression of CHR in colonic tissue of patients with active UC and assessed the effects of the CHR in dextran sulfate sodium (DSS) colitis in mice and on macrophages and human colonic epithelial cells. We found that mRNA expression of CHR correlated positively with mRNA levels of AAM markers and gene expression of tight junction (TJ) proteins and negatively with mRNA levels of interleukin (IL)-8, IL-18, and collagen in patients with active UC. Moreover, AAM markers correlated positively with gene expression of TJ proteins and negatively with IL-8, IL-18, and collagen gene expression. Experimentally, intracolonic administration of CHR protected against DSS-induced colitis by priming macrophages into AAM, reducing colonic collagen deposition, and maintaining IECs homeostasis. This effect was associated with a significant increase of AAM markers, reduction of colonic IL-18 release and conservation of gene expression of TJ proteins. In vitro, CHR enhanced AAM polarization and increased the production of anti-inflammatory mediators. CHR-treated AAM conditioned medium increased Caco-2 cell migration, viability, proliferation, and mRNA levels of TJ proteins, and decreased oxidative stress-induced apoptosis and proinflammatory cytokines release. Direct CHR treatments had the same effect. In conclusion, CHR treatment reduces the severity of colitis and the inflammatory process via enhancing AAM functions and maintaining IECs homeostasis. CHR is involved in the pathogenesis of inflammation in experimental colitis. These findings provide insight into the mechanisms of colonic inflammation and could lead to new therapeutic strategies for UC. |
| first_indexed | 2024-04-13T12:27:47Z |
| format | Article |
| id | doaj.art-365d092769404b44a8492d1bd40ff77a |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-04-13T12:27:47Z |
| publishDate | 2017-09-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-365d092769404b44a8492d1bd40ff77a2022-12-22T02:46:58ZengFrontiers Media S.A.Frontiers in Immunology1664-32242017-09-01810.3389/fimmu.2017.01131291143Chromofungin Ameliorates the Progression of Colitis by Regulating Alternatively Activated MacrophagesNour Eissa0Nour Eissa1Hayam Hussein2Laëtitia Kermarrec3Jasmine Grover4Marie-Hélène Et Metz-Boutigue5Charles N. Bernstein6Charles N. Bernstein7Jean-Eric Ghia8Jean-Eric Ghia9Jean-Eric Ghia10Jean-Eric Ghia11Immunology Department, University of Manitoba, Winnipeg, MB, CanadaChildren’s Hospital Research Institute of Manitoba, University of Manitoba, Winnipeg, MB, CanadaDepartment of Veterinary Clinical Sciences, College of Veterinary Medicine, Ohio State University, Columbus, OH, United StatesImmunology Department, University of Manitoba, Winnipeg, MB, CanadaImmunology Department, University of Manitoba, Winnipeg, MB, CanadaINSERM U977, Biomatériaux et Ingéniérie tissulaire, Institut Leriche 2éme étage, Hôpital Civil, Porte de l’Hôpital, Strasbourg, FranceRady Faculty of Health Sciences, Department of Internal Medicine, Section of Gastroenterology, University of Manitoba, Winnipeg, MB, CanadaUniversity of Manitoba IBD Clinical and Research Centre, Winnipeg, MB, CanadaImmunology Department, University of Manitoba, Winnipeg, MB, CanadaChildren’s Hospital Research Institute of Manitoba, University of Manitoba, Winnipeg, MB, CanadaRady Faculty of Health Sciences, Department of Internal Medicine, Section of Gastroenterology, University of Manitoba, Winnipeg, MB, CanadaUniversity of Manitoba IBD Clinical and Research Centre, Winnipeg, MB, CanadaUlcerative colitis (UC) is characterized by a functional dysregulation of alternatively activated macrophage (AAM) and intestinal epithelial cells (IECs) homeostasis. Chromogranin-A (CHGA) secreted by neuroendocrine cells is implicated in intestinal inflammation and immune dysregulation. CHGA undergoes proteolytic processing to generate CHGA-derived peptides. Chromofungin (CHR: CHGA47–66) is a short CHGA-derived peptide encoded by CHGA Exon-IV and is involved in innate immune regulation, but the basis is poorly investigated. We investigated the expression of CHR in colonic tissue of patients with active UC and assessed the effects of the CHR in dextran sulfate sodium (DSS) colitis in mice and on macrophages and human colonic epithelial cells. We found that mRNA expression of CHR correlated positively with mRNA levels of AAM markers and gene expression of tight junction (TJ) proteins and negatively with mRNA levels of interleukin (IL)-8, IL-18, and collagen in patients with active UC. Moreover, AAM markers correlated positively with gene expression of TJ proteins and negatively with IL-8, IL-18, and collagen gene expression. Experimentally, intracolonic administration of CHR protected against DSS-induced colitis by priming macrophages into AAM, reducing colonic collagen deposition, and maintaining IECs homeostasis. This effect was associated with a significant increase of AAM markers, reduction of colonic IL-18 release and conservation of gene expression of TJ proteins. In vitro, CHR enhanced AAM polarization and increased the production of anti-inflammatory mediators. CHR-treated AAM conditioned medium increased Caco-2 cell migration, viability, proliferation, and mRNA levels of TJ proteins, and decreased oxidative stress-induced apoptosis and proinflammatory cytokines release. Direct CHR treatments had the same effect. In conclusion, CHR treatment reduces the severity of colitis and the inflammatory process via enhancing AAM functions and maintaining IECs homeostasis. CHR is involved in the pathogenesis of inflammation in experimental colitis. These findings provide insight into the mechanisms of colonic inflammation and could lead to new therapeutic strategies for UC.http://journal.frontiersin.org/article/10.3389/fimmu.2017.01131/fullchromogranin-Agut-derived peptidesoxidative stressmucosal drug actionepithelial homeostasismacrophages switch |
| spellingShingle | Nour Eissa Nour Eissa Hayam Hussein Laëtitia Kermarrec Jasmine Grover Marie-Hélène Et Metz-Boutigue Charles N. Bernstein Charles N. Bernstein Jean-Eric Ghia Jean-Eric Ghia Jean-Eric Ghia Jean-Eric Ghia Chromofungin Ameliorates the Progression of Colitis by Regulating Alternatively Activated Macrophages Frontiers in Immunology chromogranin-A gut-derived peptides oxidative stress mucosal drug action epithelial homeostasis macrophages switch |
| title | Chromofungin Ameliorates the Progression of Colitis by Regulating Alternatively Activated Macrophages |
| title_full | Chromofungin Ameliorates the Progression of Colitis by Regulating Alternatively Activated Macrophages |
| title_fullStr | Chromofungin Ameliorates the Progression of Colitis by Regulating Alternatively Activated Macrophages |
| title_full_unstemmed | Chromofungin Ameliorates the Progression of Colitis by Regulating Alternatively Activated Macrophages |
| title_short | Chromofungin Ameliorates the Progression of Colitis by Regulating Alternatively Activated Macrophages |
| title_sort | chromofungin ameliorates the progression of colitis by regulating alternatively activated macrophages |
| topic | chromogranin-A gut-derived peptides oxidative stress mucosal drug action epithelial homeostasis macrophages switch |
| url | http://journal.frontiersin.org/article/10.3389/fimmu.2017.01131/full |
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