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Highly specific blockade of CCR5 inhibits leukocyte trafficking and reduces mucosal inflammation in murine colitis
Targeted disruption of leukocyte trafficking to the gut represents a promising approach for the treatment of inflammatory bowel diseases (IBDs). CCR5, the shared receptor for MIP1α and β and RANTES, is expressed by multiple leukocytes. Here, we aimed to determine the role of CCR5 in mediating leukoc...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4974621/ https://www.ncbi.nlm.nih.gov/pubmed/27492684 http://dx.doi.org/10.1038/srep30802 |
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author | Mencarelli, Andrea Cipriani, Sabrina Francisci, Daniela Santucci, Luca Baldelli, Franco Distrutti, Eleonora Fiorucci, Stefano |
author_facet | Mencarelli, Andrea Cipriani, Sabrina Francisci, Daniela Santucci, Luca Baldelli, Franco Distrutti, Eleonora Fiorucci, Stefano |
author_sort | Mencarelli, Andrea |
collection | PubMed |
description | Targeted disruption of leukocyte trafficking to the gut represents a promising approach for the treatment of inflammatory bowel diseases (IBDs). CCR5, the shared receptor for MIP1α and β and RANTES, is expressed by multiple leukocytes. Here, we aimed to determine the role of CCR5 in mediating leukocyte trafficking in models of colitis, and evaluate the therapeutic potential of maraviroc, an orally active CCR5 antagonist used in the treatment of CCR5-tropic HIV. Acute and chronic colitis were induced by administration of DSS or TNBS to wild-type and CCR5(−/−) mice or adoptive transfer of splenic naïve CD4(+) T-cells from wild type or CCR5(−/−) mice into RAG-1(−/−). CCR5 gene ablation reduced the mucosal recruitment and activation of CCR5-bearing CD4(+) and CD11b(+) leukocytes, resulting in profound attenuation of signs and symptoms of inflammation in the TNBS and transfer models of colitis. In the DSS/TNBS colitis and in the transfer model, maraviroc attenuated development of intestinal inflammation by selectively reducing the recruitment of CCR5 bearing leukocytes. In summary, CCR5 regulates recruitment of blood leukocytes into the colon indicating that targeting CCR5 may offer therapeutic options in IBDs. |
format | Online Article Text |
id | pubmed-4974621 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-49746212016-08-17 Highly specific blockade of CCR5 inhibits leukocyte trafficking and reduces mucosal inflammation in murine colitis Mencarelli, Andrea Cipriani, Sabrina Francisci, Daniela Santucci, Luca Baldelli, Franco Distrutti, Eleonora Fiorucci, Stefano Sci Rep Article Targeted disruption of leukocyte trafficking to the gut represents a promising approach for the treatment of inflammatory bowel diseases (IBDs). CCR5, the shared receptor for MIP1α and β and RANTES, is expressed by multiple leukocytes. Here, we aimed to determine the role of CCR5 in mediating leukocyte trafficking in models of colitis, and evaluate the therapeutic potential of maraviroc, an orally active CCR5 antagonist used in the treatment of CCR5-tropic HIV. Acute and chronic colitis were induced by administration of DSS or TNBS to wild-type and CCR5(−/−) mice or adoptive transfer of splenic naïve CD4(+) T-cells from wild type or CCR5(−/−) mice into RAG-1(−/−). CCR5 gene ablation reduced the mucosal recruitment and activation of CCR5-bearing CD4(+) and CD11b(+) leukocytes, resulting in profound attenuation of signs and symptoms of inflammation in the TNBS and transfer models of colitis. In the DSS/TNBS colitis and in the transfer model, maraviroc attenuated development of intestinal inflammation by selectively reducing the recruitment of CCR5 bearing leukocytes. In summary, CCR5 regulates recruitment of blood leukocytes into the colon indicating that targeting CCR5 may offer therapeutic options in IBDs. Nature Publishing Group 2016-08-05 /pmc/articles/PMC4974621/ /pubmed/27492684 http://dx.doi.org/10.1038/srep30802 Text en Copyright © 2016, The Author(s) http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ |
spellingShingle | Article Mencarelli, Andrea Cipriani, Sabrina Francisci, Daniela Santucci, Luca Baldelli, Franco Distrutti, Eleonora Fiorucci, Stefano Highly specific blockade of CCR5 inhibits leukocyte trafficking and reduces mucosal inflammation in murine colitis |
title | Highly specific blockade of CCR5 inhibits leukocyte trafficking and reduces mucosal inflammation in murine colitis |
title_full | Highly specific blockade of CCR5 inhibits leukocyte trafficking and reduces mucosal inflammation in murine colitis |
title_fullStr | Highly specific blockade of CCR5 inhibits leukocyte trafficking and reduces mucosal inflammation in murine colitis |
title_full_unstemmed | Highly specific blockade of CCR5 inhibits leukocyte trafficking and reduces mucosal inflammation in murine colitis |
title_short | Highly specific blockade of CCR5 inhibits leukocyte trafficking and reduces mucosal inflammation in murine colitis |
title_sort | highly specific blockade of ccr5 inhibits leukocyte trafficking and reduces mucosal inflammation in murine colitis |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4974621/ https://www.ncbi.nlm.nih.gov/pubmed/27492684 http://dx.doi.org/10.1038/srep30802 |
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