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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Published in | Frontiers in immunology Vol. 12; p. 618365 |
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Main Authors | , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
Frontiers Media S.A
09.08.2021
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Subjects | |
Online Access | Get full text |
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Summary: | 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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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Reviewed by: Li Yang, East Carolina University, United States; Makoto Makishima, Nihon University, Japan This article was submitted to Mucosal Immunity, a section of the journal Frontiers in Immunology Edited by: Mats Bemark, University of Gothenburg, Sweden |
ISSN: | 1664-3224 1664-3224 |
DOI: | 10.3389/fimmu.2021.618365 |