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Kaempferol Attenuates Gouty Arthritis by Regulating the Balance of Th17/Treg Cells and Secretion of IL-17

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Abstract—

Kaempferol is a common flavonoid aglycone widely found in plants. It exhibits beneficial therapeutic effects in the treatment of arthritis. However, the effects of kaempferol on gouty arthritis (GA) have not been verified. This study aimed to explore the potential mechanisms by which kaempferol regulates GA by network pharmacology and experimental validation. Potential drug targets for GA were identified with a protein–protein interaction network. Then, we performed a KEGG pathway analysis to elucidate the major pathway involved in the kaempferol-mediated treatment of GA. In addition, the molecular docking was performed. A rat model of GA was constructed to verify the results of network pharmacology analysis and investigate the mechanism of kaempferol against GA. The network pharmacology study indicated that there were 275 common targets of kaempferol and GA treatment. Kaempferol exerted therapeutic effects on GA, in part, by regulating the IL-17, AGE-RAGE, p53, TNF, and FoxO signaling pathways. Molecular docking results showed that kaempferol stably docked with the core MMP9, ALB, CASP3, TNF, VEGFA, CCL2, CXCL8, AKT1, JUN, and INS. Experimental validation suggested that kaempferol eased MSU-induced mechanical allodynia, ankle edema, and inflammation. It significantly suppressed the expression of IL-1β, IL-6, TNF-α, and TGF-β1 and restored Th17/Treg imbalance in MSU-induced rats and IL-6-induced PBMCs. Kaempferol also affected RORγt and Foxp3 through IL-17 pathway. The present study clarifies the mechanism of kaempferol against GA and provides evidence to support its clinical use.

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Data Availability

The data used to support the findings of this study will be available from the corresponding author upon request.

Abbreviations

BC:

Betweenness centrality

BCA:

Bicinchoninic acid

BP:

Biological process

CC:

Closeness centrality

DC:

Degree centrality

DMSO:

Dimethyl sulfoxide

EDTA:

Ethylenediaminetetraacetic acid

Foxp3:

Forkhead box p3

GA:

Gouty arthritis

GAPDH:

Glyceraldehyde-3-phosphate dehydrogenase

GO:

Gene ontology

H&E:

Hematoxylin and eosin

IL:

Interleukin

KEGG:

Kyoto encyclopedia of genes and genomes

MCC:

Maximal clique centrality

MF:

Molecular function

MSU:

Monosodium urate

NF-κB:

Nuclear factor-κ-gene binding

PBMC:

Peripheral blood mononuclear cell

PBS:

Phosphate-buffered saline

PPI:

Protein–protein interaction

RORγt:

Retinoid-related orphan nuclear receptor γt

SD:

Sprague Dawley

TCMSP:

Traditional chinese medicine database and analysis platform;

TGF-β:

Transforming growth facter-β1

TLR:

Toll-like receptors

TNF:

Tumor necrosis factor

TTD:

Therapeutic target database

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Funding

This research was financially supported by National Natural Science Foundation of China (NSFC) (NO. 82274390); Guangzhou Science and Technology Plan Project (NO. 2023A04J1289); Natural Science Foundation of Guangdong Province (NO. 2019A1515011636, 2022A1515110789); Guangzhou Key Laboratory of Formula-Pattern of Traditional Chinese Medicine (NO. 202102010014).

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Author notes

  1. Nan Li, Shulin Chen, and Weiqing Deng have contributed equally to this work and share first authorship.

Authors and Affiliations

  1. School of Traditional Chinese Medicine, Jinan University, Guangzhou, 510632, China

    Nan Li & Yu Guo

  2. The First Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, 510405, China

    Shulin Chen, Zhaohui Gong & Qiang Xu

  3. Department of Rheumatology, the First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, 510405, China

    Shulin Chen & Qiang Xu

  4. College of Pharmacy, Jinan University, Guangzhou, 510632, China

    Weiqing Deng

  5. Department of Cardiovascular, the First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, 510405, China

    Zhaohui Gong

  6. Department of Rheumatology, the First Affiliated Hospital of Jinan University, Guangzhou, 510632, China

    Shan Zeng

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Contributions

QX, SZ, and YG designed and supervised the experiments. NL, SC, and WD conducted the experiments. WD and ZG analyzed the data and prepared the manuscript. NL and QX reviewed and revised the manuscript.

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Correspondence to Yu Guo, Shan Zeng or Qiang Xu.

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Li, N., Chen, S., Deng, W. et al. Kaempferol Attenuates Gouty Arthritis by Regulating the Balance of Th17/Treg Cells and Secretion of IL-17. Inflammation 46, 1901–1916 (2023). https://doi.org/10.1007/s10753-023-01849-8

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