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Title: | Phloretin suppresses neuroinflammation by autophagy-mediated Nrf2 activation in macrophages | Authors: | DIERCKX, Tess HAIDAR, Mansour GRAJCHEN, Elien WOUTERS, Elien VANHERLE, Sam LOIX, Melanie Boeykens, Annick Bylemans, Dany Hardonniere, Kevin Kerdine-Romer, Saadia BOGIE, Jeroen HENDRIKS, Jerome |
Issue Date: | 2021 | Publisher: | BMC | Source: | Journal of neuroinflammation, 18 (1) (Art N° 148) | Abstract: | Background Macrophages play a dual role in neuroinflammatory disorders such as multiple sclerosis (MS). They are involved in lesion onset and progression but can also promote the resolution of inflammation and repair of damaged tissue. In this study, we investigate if and how phloretin, a flavonoid abundantly present in apples and strawberries, lowers the inflammatory phenotype of macrophages and suppresses neuroinflammation. Methods Transcriptional changes in mouse bone marrow-derived macrophages upon phloretin exposure were assessed by bulk RNA sequencing. Underlying pathways related to inflammation, oxidative stress response and autophagy were validated by quantitative PCR, fluorescent and absorbance assays, nuclear factor erythroid 2-related factor 2 (Nrf2) knockout mice, western blot, and immunofluorescence. The experimental autoimmune encephalomyelitis (EAE) model was used to study the impact of phloretin on neuroinflammation in vivo and confirm underlying mechanisms. Results We show that phloretin reduces the inflammatory phenotype of macrophages and markedly suppresses neuroinflammation in EAE. Phloretin mediates its effect by activating the Nrf2 signaling pathway. Nrf2 activation was attributed to 5 ' AMP-activated protein kinase (AMPK)-dependent activation of autophagy and subsequent kelch-like ECH-associated protein 1 (Keap1) degradation. Conclusions This study opens future perspectives for phloretin as a therapeutic strategy for neuroinflammatory disorders such as MS. | Notes: | Hendriks, JJA (corresponding author), Hasselt Univ, Biomed Res Inst, Dept Immunol & Infect, Diepenbeek, Belgium. Jerome.hendriks@uhasselt.be |
Keywords: | Phloretin;Macrophages;Neuroinflammation;Multiple sclerosis;Autoimmunity | Document URI: | http://hdl.handle.net/1942/35721 | e-ISSN: | 1742-2094 | DOI: | 10.1186/s12974-021-02194-z | ISI #: | WOS:000671863100001 | Rights: | The Author(s). 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, | Category: | A1 | Type: | Journal Contribution | Validations: | ecoom 2022 |
Appears in Collections: | Research publications |
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s12974-021-02194-z.pdf | Published version | 5.04 MB | Adobe PDF | View/Open |
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