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Phloretin suppresses neuroinflammation by autophagy-mediated Nrf2 activation in macrophages

Tess Dierckx1, Mansour Haidar1, Elien Grajchen1

  • 1Department of Immunology and Infection, Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium.

Journal of Neuroinflammation
|July 5, 2021
PubMed
Abstract

Insights

Phloretin, a natural flavonoid, reduces macrophage inflammation and neuroinflammation. It activates the Nrf2 pathway via AMPK-dependent autophagy, offering therapeutic potential for multiple sclerosis (MS).

Area of Science:

  • Neuroimmunology
  • Molecular Biology
  • Pharmacology

Background:

  • Macrophages exhibit dual roles in neuroinflammatory disorders like multiple sclerosis (MS), contributing to both disease progression and resolution.
  • Phloretin, a flavonoid found in fruits, is investigated for its potential to modulate macrophage inflammatory phenotypes and neuroinflammation.

Purpose of the Study:

  • To investigate the effects of phloretin on macrophage inflammatory phenotype.
  • To determine phloretin's impact on neuroinflammation in vivo.
  • To elucidate the molecular mechanisms underlying phloretin's actions.

Main Methods:

  • Bulk RNA sequencing of mouse bone marrow-derived macrophages exposed to phloretin.
  • Validation of inflammatory, oxidative stress, and autophagy pathways using qPCR, assays, Nrf2 knockout mice, Western blot, and immunofluorescence.
  • Assessment of phloretin's efficacy in the experimental autoimmune encephalomyelitis (EAE) model.

Main Results:

  • Phloretin significantly reduces macrophage inflammatory phenotype and suppresses neuroinflammation in the EAE model.
  • Phloretin-induced effects are mediated by the activation of the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway.
  • Nrf2 activation is linked to 5' AMP-activated protein kinase (AMPK)-dependent autophagy and subsequent kelch-like ECH-associated protein 1 (Keap1) degradation.

Conclusions:

  • Phloretin demonstrates potential as a therapeutic agent for neuroinflammatory conditions.
  • The study highlights the Nrf2 pathway as a key mediator of phloretin's anti-inflammatory effects in macrophages.
  • Future research can explore phloretin's clinical applications for diseases like multiple sclerosis.
Keywords:
AutoimmunityMacrophagesMultiple sclerosisNeuroinflammationPhloretin

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