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Peroxisome Proliferator-Activated Receptor Alpha Mediates the Beneficial Effects of Atorvastatin in Experimental Colitis

The current therapeutic options for Inflammatory Bowel Diseases (IBD) are limited. Even using common anti-inflammatory, immunosuppressive or biological therapies, many patients become unresponsive to the treatments, immunosuppressed or unable to restrain secondary infections. Statins are cholesterol...

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Autores principales: Basso, Paulo José, Sales-Campos, Helioswilton, Nardini, Viviani, Duarte-Silva, Murillo, Alves, Vanessa Beatriz Freitas, Bonfá, Giuliano, Rodrigues, Cassiano Costa, Ghirotto, Bruno, Chica, Javier Emílio Lazo, Nomizo, Auro, Cardoso, Cristina Ribeiro de Barros
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8382038/
https://www.ncbi.nlm.nih.gov/pubmed/34434187
http://dx.doi.org/10.3389/fimmu.2021.618365
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author Basso, Paulo José
Sales-Campos, Helioswilton
Nardini, Viviani
Duarte-Silva, Murillo
Alves, Vanessa Beatriz Freitas
Bonfá, Giuliano
Rodrigues, Cassiano Costa
Ghirotto, Bruno
Chica, Javier Emílio Lazo
Nomizo, Auro
Cardoso, Cristina Ribeiro de Barros
author_facet Basso, Paulo José
Sales-Campos, Helioswilton
Nardini, Viviani
Duarte-Silva, Murillo
Alves, Vanessa Beatriz Freitas
Bonfá, Giuliano
Rodrigues, Cassiano Costa
Ghirotto, Bruno
Chica, Javier Emílio Lazo
Nomizo, Auro
Cardoso, Cristina Ribeiro de Barros
author_sort Basso, Paulo José
collection PubMed
description The current therapeutic options for Inflammatory Bowel Diseases (IBD) are limited. Even using common anti-inflammatory, immunosuppressive or biological therapies, many patients become unresponsive to the treatments, immunosuppressed or unable to restrain secondary infections. Statins are cholesterol-lowering drugs with non-canonical anti-inflammatory properties, whose underlying mechanisms of action still remain poorly understood. Here, we described that in vitro atorvastatin (ATO) treatment was not toxic to splenocytes, constrained cell proliferation and modulated IL-6 and IL-10 production in a dose-dependent manner. Mice exposed to dextran sulfate sodium (DSS) for colitis induction and treated with ATO shifted their immune response from Th17 towards Th2, improved the clinical and histological aspects of intestinal inflammation and reduced the number of circulating leukocytes. Both experimental and in silico analyses revealed that PPAR-α expression is reduced in experimental colitis, which was reversed by ATO treatment. While IBD patients also downregulate PPAR-α expression, the responsiveness to biological therapy relied on the restoration of PPAR-α levels. Indeed, the in vitro and in vivo effects induced by ATO treatment were abrogated in Ppara (-/-) mice or leukocytes. In conclusion, the beneficial effects of ATO in colitis are dependent on PPAR-α, which could also be a potential predictive biomarker of therapy responsiveness in IBD.
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spelling pubmed-83820382021-08-24 Peroxisome Proliferator-Activated Receptor Alpha Mediates the Beneficial Effects of Atorvastatin in Experimental Colitis Basso, Paulo José Sales-Campos, Helioswilton Nardini, Viviani Duarte-Silva, Murillo Alves, Vanessa Beatriz Freitas Bonfá, Giuliano Rodrigues, Cassiano Costa Ghirotto, Bruno Chica, Javier Emílio Lazo Nomizo, Auro Cardoso, Cristina Ribeiro de Barros Front Immunol Immunology The current therapeutic options for Inflammatory Bowel Diseases (IBD) are limited. Even using common anti-inflammatory, immunosuppressive or biological therapies, many patients become unresponsive to the treatments, immunosuppressed or unable to restrain secondary infections. Statins are cholesterol-lowering drugs with non-canonical anti-inflammatory properties, whose underlying mechanisms of action still remain poorly understood. Here, we described that in vitro atorvastatin (ATO) treatment was not toxic to splenocytes, constrained cell proliferation and modulated IL-6 and IL-10 production in a dose-dependent manner. Mice exposed to dextran sulfate sodium (DSS) for colitis induction and treated with ATO shifted their immune response from Th17 towards Th2, improved the clinical and histological aspects of intestinal inflammation and reduced the number of circulating leukocytes. Both experimental and in silico analyses revealed that PPAR-α expression is reduced in experimental colitis, which was reversed by ATO treatment. While IBD patients also downregulate PPAR-α expression, the responsiveness to biological therapy relied on the restoration of PPAR-α levels. Indeed, the in vitro and in vivo effects induced by ATO treatment were abrogated in Ppara (-/-) mice or leukocytes. In conclusion, the beneficial effects of ATO in colitis are dependent on PPAR-α, which could also be a potential predictive biomarker of therapy responsiveness in IBD. Frontiers Media S.A. 2021-08-09 /pmc/articles/PMC8382038/ /pubmed/34434187 http://dx.doi.org/10.3389/fimmu.2021.618365 Text en Copyright © 2021 Basso, Sales-Campos, Nardini, Duarte-Silva, Alves, Bonfá, Rodrigues, Ghirotto, Chica, Nomizo and Cardoso https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Basso, Paulo José
Sales-Campos, Helioswilton
Nardini, Viviani
Duarte-Silva, Murillo
Alves, Vanessa Beatriz Freitas
Bonfá, Giuliano
Rodrigues, Cassiano Costa
Ghirotto, Bruno
Chica, Javier Emílio Lazo
Nomizo, Auro
Cardoso, Cristina Ribeiro de Barros
Peroxisome Proliferator-Activated Receptor Alpha Mediates the Beneficial Effects of Atorvastatin in Experimental Colitis
title Peroxisome Proliferator-Activated Receptor Alpha Mediates the Beneficial Effects of Atorvastatin in Experimental Colitis
title_full Peroxisome Proliferator-Activated Receptor Alpha Mediates the Beneficial Effects of Atorvastatin in Experimental Colitis
title_fullStr Peroxisome Proliferator-Activated Receptor Alpha Mediates the Beneficial Effects of Atorvastatin in Experimental Colitis
title_full_unstemmed Peroxisome Proliferator-Activated Receptor Alpha Mediates the Beneficial Effects of Atorvastatin in Experimental Colitis
title_short Peroxisome Proliferator-Activated Receptor Alpha Mediates the Beneficial Effects of Atorvastatin in Experimental Colitis
title_sort peroxisome proliferator-activated receptor alpha mediates the beneficial effects of atorvastatin in experimental colitis
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8382038/
https://www.ncbi.nlm.nih.gov/pubmed/34434187
http://dx.doi.org/10.3389/fimmu.2021.618365
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