2. Academic Validation
  3. Kaempferol improves depression-like behaviors through shifting microglia polarization and suppressing NLRP3 via tilting the balance of PPARγ and STAT1 signaling

Kaempferol improves depression-like behaviors through shifting microglia polarization and suppressing NLRP3 via tilting the balance of PPARγ and STAT1 signaling

  • Int Immunopharmacol. 2024 Nov 3;143(Pt 3):113538. doi: 10.1016/j.intimp.2024.113538.
Pan Su 1,  Liming Liu 2,  Yuhang Gong 3,  Shuaijun Peng 4,  Xiangli Yan 5,  Ming Bai 6,  Erping Xu 7,  Yucheng Li 8
Affiliations

Affiliations

  • 1 Collaborative Innovation Center of Research and Development on the Whole Industry Chain of Yu-Yao, Henan University of Chinese Medicine, Henan Province, Zhengzhou 450046, PR China; Academy of Chinese Medical Sciences, Henan University of Chinese Medicine, Zhengzhou 450046, PR China. Electronic address: Supan@hactcm.edu.cn.
  • 2 Collaborative Innovation Center of Research and Development on the Whole Industry Chain of Yu-Yao, Henan University of Chinese Medicine, Henan Province, Zhengzhou 450046, PR China; College of Pharmacy, Henan University of Chinese Medicine, Zhengzhou 450046, PR China. Electronic address: 15265338149@163.com.
  • 3 Collaborative Innovation Center of Research and Development on the Whole Industry Chain of Yu-Yao, Henan University of Chinese Medicine, Henan Province, Zhengzhou 450046, PR China; Academy of Chinese Medical Sciences, Henan University of Chinese Medicine, Zhengzhou 450046, PR China. Electronic address: gongyuhangcpu@163.com.
  • 4 Collaborative Innovation Center of Research and Development on the Whole Industry Chain of Yu-Yao, Henan University of Chinese Medicine, Henan Province, Zhengzhou 450046, PR China; College of Pharmacy, Henan University of Chinese Medicine, Zhengzhou 450046, PR China. Electronic address: ShuaijunPeng1214@126.com.
  • 5 Collaborative Innovation Center of Research and Development on the Whole Industry Chain of Yu-Yao, Henan University of Chinese Medicine, Henan Province, Zhengzhou 450046, PR China; Academy of Chinese Medical Sciences, Henan University of Chinese Medicine, Zhengzhou 450046, PR China. Electronic address: Yanxiangli@hactcm.edu.cn.
  • 6 Collaborative Innovation Center of Research and Development on the Whole Industry Chain of Yu-Yao, Henan University of Chinese Medicine, Henan Province, Zhengzhou 450046, PR China; Academy of Chinese Medical Sciences, Henan University of Chinese Medicine, Zhengzhou 450046, PR China. Electronic address: Baiming666@126.com.
  • 7 Collaborative Innovation Center of Research and Development on the Whole Industry Chain of Yu-Yao, Henan University of Chinese Medicine, Henan Province, Zhengzhou 450046, PR China; Academy of Chinese Medical Sciences, Henan University of Chinese Medicine, Zhengzhou 450046, PR China. Electronic address: Xuerping0371@163.com.
  • 8 Collaborative Innovation Center of Research and Development on the Whole Industry Chain of Yu-Yao, Henan University of Chinese Medicine, Henan Province, Zhengzhou 450046, PR China; Academy of Chinese Medical Sciences, Henan University of Chinese Medicine, Zhengzhou 450046, PR China. Electronic address: Liyucheng@hactcm.edu.cn.
PMID: 39492132 DOI: 10.1016/j.intimp.2024.113538
Abstract

Background: The pathogenesis of depression is largely influenced by dyshomeostasis of neuroinflammation regulated by microglia M1/M2 polarization, and NLRP3 inflammasome acts critical roles in shifting microglia polarization. Kaempferol (Kae), a major flavonoid in edible Plants, possesses anti-inflammation and anti-depression capacity, but its underlying cellular and molecular mechanisms of antidepressive effect have not yet fully explored.

Methods: In vivo studies with lipopolysaccharide (LPS)-induced depressive mice were carried out to evaluate antidepressant effect of Kae. In vitro, BV2 microglia cell line stimulated by LPS along with IFN-γ to detect pharmacological effects of Kae on microglia polarization and NLRP3. Based on two depression-related GEO datasets (GSE54570 and GSE54568) and the potential targets of Kae obtained from GeneCards database, enrichment analysis and protein-protein interaction (PPI) network construction reveal potential therapeutic targets of Kae for depression. Then the precise antidepressant mechanisms of Kae were verified by western blot and immunofluorescent staining in vivo and vitro.

Results: Our results showed that Kae significantly improves LPS-induced depressive behaviors and alleviates neuroinflammation in prefrontal cortex. Moreover, Kae obviously shifted microglia polarization to M2 phenotype, and also suppressed NLRP3 in prefrontal cortex and BV2. Enrichment analysis and PPI network construction suggested PPARγ and STAT1 signaling are related to regulation of NLRP3 in depression. Furtherly, Kae remarkably enhanced PPARγ activation and inhibited nuclear translocation of p-STAT1 in microglia of prefrontal cortex and BV2. Importantly, pre-incubation with PPARγ Antagonist T0070907 or overexpression with CASTAT1 (constitutively active STAT1) both prevented pharmacologic effects of Kae on shifting microglia polarization and suppressing NLRP3 in BV2. Noteworthily, T0070907 significantly blocked the inhibitory effect of Kae on STAT1 while overexpression with CASTAT1 abolished the effect of Kae on PPARγ activation in BV2. Above results suggested that pharmacologic effects of Kae on microglia polarization and NLRP3 are dependent on the balance of counter-regulatory PPARγ and STAT1 signaling.

Conclusion: Our results indicated that the shifting microglia polarization and suppression of NLRP3 via tilting the balance of PPARγ and STAT1 signaling may be the antidepressant mechanism of Kae, which provides a novel perspective for elucidating antidepressive effect of Kae.

Keywords

Anti-depression; Kaempferol; M1/M2 polarization; NLRP3 inflammasome; PPARγ and STAT1 signaling.

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