Microglial forkhead box O3a deficiency attenuates LPS-induced neuro-inflammation and depressive-like behaviour through regulating the expression of peroxisome proliferator-activated receptor-γ

  • Br J Pharmacol. 2024 Jun 16. doi: 10.1111/bph.16474.
Rikang Wang  1 ,  Lianru Ji  2 ,  Shun Yuan  2 ,  Xiamin Liu  2 ,  Zhi Liang  1 ,  Wenjing Chen  1 ,  Bocheng Wang  1 ,  Suifa Hu  2 ,  Zhiping Liu  3  4 ,  Zhiwen Zeng  5 ,  Yonggui Song  2 ,  Tao Wu  1 ,  Baodong Chen  1
Affiliations
  • 1. Department of Neurosurgery, Peking University Shenzhen Hospital, Shenzhen, China.
  • 2. Key Laboratory of Evaluation of Traditional Chinese Medicine Efficacy (Prevention and Treatment of Brain Disease with Mental Disorders); Key Laboratory of Depression Animal Model Based on TCM syndrome, Jiangxi Administration of Traditional Chinese Medicine; Key Laboratory of TCM for Prevention and Treatment of Brain Diseases with Cognitive Dysfunction, Jiangxi University of Chinese Medicine, Nanchang, China.
  • 3. State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou, China.
  • 4. Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou, China.
  • 5. Department for Bipolar Disorders, Shenzhen Kangning Hospital, Shenzhen Mental Health Center, Shenzhen, China.
PMID: 38881194 DOI: 10.1111/bph.16474
Abstract

Background and purpose: Depression is closely linked with microglial activation and neuro-inflammation. Peroxisome proliferator-activated receptor-γ (PPAR-γ) plays an important role in M2 activation of microglia. Forkhead box (FOX) O3a has been implicated in the regulation of mood-relevant behaviour. However, little is known about the inflammatory mechanisms of in the microglia of the brain. Here, we have investigated the role of microglial FOXO3a/PPAR-γ in the development of depression.

Experimental approach: The effect of FOXO3a on microglia inflammation was analysed in vitro and in lipopolysaccharide (LPS)-induced depression-like behaviours in vivo. ChIP-seq and Dual-luciferase reporter assays were used to confirm the interaction between FOXO3a and PPAR-γ. Behavioural changes were measured, while inflammatory cytokines, microglial phenotype and morphological properties were determined by ELISA, qRT-PCR, western blotting and immunostaining.

Key results: Overexpression of FOXO3a significantly attenuated expression of PPAR-γ and enhanced the microglial polarization towards the M1 phenotype, while knockdown of FOXO3a had the opposite effect. FOXO3a binds to the promoters of PPAR-γ and decreases its transcription activity. Importantly, deacetylation and activation of FOXO3a regulate LPS-induced neuro-inflammation by inhibiting the expression of PPAR-γ in microglia cells, supporting the antidepressant potential of histone deacetylase inhibitors. Microglial FOXO3a deficiency in mice alleviated LPS-induced neuro-inflammation and depression-like behaviours but failed to reduce anxiety behaviour, whereas pharmacological inhibition of PPAR-γ by GW9662 restored LPS-induced microglial activation and depressive-like behaviours in microglial FOXO3a-deficient mice.

Conclusion and implications: FOXO3a/PPAR-γ axis plays an important role in microglial activation and depression, identifying a new therapeutic avenue for the treatment of major depression.

Keywords
FOXO3a; PPAR‐γ; depression; inflammation; microglia.
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