Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Mencarelli, Andrea, Cipriani, Sabrina, Francisci, Daniela, Santucci, Luca, Baldelli, Franco, Distrutti, Eleonora, Fiorucci, Stefano
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2016
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
_version_ 1782446576166240256
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
work_keys_str_mv AT mencarelliandrea highlyspecificblockadeofccr5inhibitsleukocytetraffickingandreducesmucosalinflammationinmurinecolitis
AT ciprianisabrina highlyspecificblockadeofccr5inhibitsleukocytetraffickingandreducesmucosalinflammationinmurinecolitis
AT franciscidaniela highlyspecificblockadeofccr5inhibitsleukocytetraffickingandreducesmucosalinflammationinmurinecolitis
AT santucciluca highlyspecificblockadeofccr5inhibitsleukocytetraffickingandreducesmucosalinflammationinmurinecolitis
AT baldellifranco highlyspecificblockadeofccr5inhibitsleukocytetraffickingandreducesmucosalinflammationinmurinecolitis
AT distruttieleonora highlyspecificblockadeofccr5inhibitsleukocytetraffickingandreducesmucosalinflammationinmurinecolitis
AT fioruccistefano highlyspecificblockadeofccr5inhibitsleukocytetraffickingandreducesmucosalinflammationinmurinecolitis