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BMC Complementary Medicine and Therapies

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Open Access 01-12-2024 | Rheumatoid Arthritis | Research

Inhibition of IL-17 signaling in macrophages underlies the anti-arthritic effects of halofuginone hydrobromide: Network pharmacology, molecular docking, and experimental validation

Authors: Junping Zhu, Jiaming Wei, Ye Lin, Yuanyuan Tang, Zhaoli Su, Liqing Li, Bin Liu, Xiong Cai

Published in: BMC Complementary Medicine and Therapies | Issue 1/2024

Abstract

Background

Rheumatoid arthritis (RA) is a prevalent autoimmune disease marked by chronic synovitis as well as cartilage and bone destruction. Halofuginone hydrobromide (HF), a bioactive compound derived from the Chinese herbal plant Dichroa febrifuga Lour., has demonstrated substantial anti-arthritic effects in RA. Nevertheless, the molecular mechanisms responsible for the anti-RA effects of HF remain unclear.

Methods

This study employed a combination of network pharmacology, molecular docking, and experimental validation to investigate potential targets of HF in RA.

Results

Network pharmacology analyses identified 109 differentially expressed genes (DEGs) resulting from HF treatment in RA. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses unveiled a robust association between these DEGs and the IL-17 signaling pathway. Subsequently, a protein-protein interaction (PPI) network analysis revealed 10 core DEGs, that is, EGFR, MMP9, TLR4, ESR1, MMP2, PPARG, MAPK1, JAK2, STAT1, and MAPK8. Among them, MMP9 displayed the greatest binding energy for HF. In an in vitro assay, HF significantly inhibited the activity of inflammatory macrophages, and regulated the IL-17 signaling pathway by decreasing the levels of IL-17 C, p-NF-κB, and MMP9.

Conclusion

In summary, these findings suggest that HF has the potential to inhibit the activation of inflammatory macrophages through its regulation of the IL-17 signaling pathway, underscoring its potential in the suppression of immune-mediated inflammation in RA.

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Conigliaro P, Chimenti M, Triggianese P, Sunzini F, Novelli L, Perricone C, Perricone R. Autoantibodies in inflammatory arthritis. Autoimmun rev. 2016;15:673–83. https://doi.org/10.1016/j.autrev.2016.03.003.CrossRefPubMed

Di Matteo A, Bathon JM, Emery P. Rheumatoid arthritis. Lancet. 2023;402:2019–33. https://doi.org/10.1016/S0140-6736(23)01525-8.CrossRefPubMed

Dissanayake K, Jayasinghe C, Wanigasekara P, Sominanda A. Potential applicability of cytokines as biomarkers of disease activity in rheumatoid arthritis: enzyme-linked immunosorbent spot assay-based evaluation of TNF-α, IL-1β, IL-10 and IL-17A. PLoS ONE. 2021;16:e0246111. https://doi.org/10.1371/journal.pone.0246111.CrossRefPubMedPubMedCentral

Siouti E, Andreakos E. The many facets of macrophages in rheumatoid arthritis. Biochem Pharmacol. 2019;165:152–69. https://doi.org/10.1016/j.bcp.2019.03.029.CrossRefPubMed

Zhao J, Guo S, Schrodi S, He D. Molecular and Cellular Heterogeneity in Rheumatoid Arthritis: mechanisms and clinical implications. Front Immunol. 2021;12:790122. https://doi.org/10.3389/fimmu.2021.790122.CrossRefPubMedPubMedCentral

Smolen JS, Landewé RBM, Bijlsma JWJ, Burmester GR, Dougados M, Kerschbaumer A, McInnes IB, Sepriano A, Vollenhoven RFv W, Md, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2019 update. Ann Rheum Dis. 2020;79:685–99. https://doi.org/10.1136/annrheumdis-2019-216655.CrossRefPubMed

Pines M, Spector I. Halofuginone - the multifaceted molecule. Molecules. 2015;20:573–94. https://doi.org/10.3390/molecules20010573.CrossRefPubMedPubMedCentral

Zhan W, Kang Y, Chen N, Mao C, Kang Y, Shang J. Halofuginone ameliorates inflammation in severe acute hepatitis B virus (HBV)-infected SD rats through AMPK activation. Drug design, development and therapy. 2017; 11: 2947–55. https://doi.org/10.2147/dddt.s149623.

Park M, Park J, Park E, Lim M, Kim S, Lee D, Baek S, Yang E, Woo J, Lee J, et al. Halofuginone ameliorates autoimmune arthritis in mice by regulating the balance between Th17 and Treg cells and inhibiting osteoclastogenesis. Arthritis Rheumatol (Hoboken NJ). 2014;66:1195–207. https://doi.org/10.1002/art.38313.CrossRef

10.

Zeng S, Wang K, Huang M, Qiu Q, Xiao Y, Shi M, Zou Y, Yang X, Xu H, Liang L. Halofuginone inhibits TNF-α-induced the migration and proliferation of fibroblast-like synoviocytes from rheumatoid arthritis patients. Int Immunopharmacol. 2017;43:187–94. https://doi.org/10.1016/j.intimp.2016.12.016.CrossRefPubMed

11.

Hou Y, Wei D, Zhang Z, Lei T, Li S, Bao J, Guo H, Tan L, Xie X, Zhuang Y, et al. Downregulation of nutrition sensor GCN2 in macrophages contributes to poor wound healing in diabetes. Cell Rep. 2024;43:113658. https://doi.org/10.1016/j.celrep.2023.113658.CrossRefPubMed

12.

Liu J, Hua Z, Liao S, Li B, Tang S, Huang Q, Wei Z, Lu R, Lin C, Ding X. Prediction of the active compounds and mechanism of Biochanin A in the treatment of Legg-Calvé-Perthes disease based on network pharmacology and molecular docking. BMC Complement Med Ther. 2024;24:26. https://doi.org/10.1186/s12906-023-04298-w.CrossRefPubMedPubMedCentral

13.

Hopkins A. Network pharmacology: the next paradigm in drug discovery. Nat Chem Biol. 2008;4:682–90. https://doi.org/10.1038/nchembio.118.CrossRefPubMed

14.

Wang Y, Bryant S, Cheng T, Wang J, Gindulyte A, Shoemaker B, Thiessen P, He S, Zhang J. PubChem BioAssay: 2017 update. Nucleic Acids Res. 2017;45:D955–63. https://doi.org/10.1093/nar/gkw1118.CrossRefPubMed

15.

Wang X, Shen Y, Wang S, Li S, Zhang W, Liu X, Lai L, Pei J, Li H. PharmMapper 2017 update: a web server for potential drug target identification with a comprehensive target pharmacophore database. Nucleic Acids Res. 2017;45:W356–60. https://doi.org/10.1093/nar/gkx374.CrossRefPubMedPubMedCentral

16.

Gallo K, Goede A, Preissner R, Gohlke B. SuperPred 3.0: drug classification and target prediction-a machine learning approach. Nucleic Acids Res. 2022;50:W726–31. https://doi.org/10.1093/nar/gkac297.CrossRefPubMedPubMedCentral

17.

Amberger J, Bocchini C, Hamosh A. A new face and new challenges for online mendelian inheritance in man (OMIM®). Hum Mutat. 2011;32:564–7. https://doi.org/10.1002/humu.21466.CrossRefPubMed

18.

Fishilevich S, Zimmerman S, Kohn A, Iny Stein T, Olender T, Kolker E, Safran M, Lancet D. Genic insights from integrated human proteomics in GeneCards. Database: the journal of biological databases and curation. 2016; 2016: baw030. https://doi.org/10.1093/database/baw030.

19.

Wang Y, Zhang S, Li F, Zhou Y, Zhang Y, Wang Z, Zhang R, Zhu J, Ren Y, Tan Y, et al. Therapeutic target database 2020: enriched resource for facilitating research and early development of targeted therapeutics. Nucleic Acids Res. 2020;48:D1031–41. https://doi.org/10.1093/nar/gkz981.CrossRefPubMed

20.

Sayers E, Beck J, Bolton E, Bourexis D, Brister J, Canese K, Comeau D, Funk K, Kim S, Klimke W, et al. Database resources of the National Center for Biotechnology Information. Nucleic Acids Res. 2021;49:D10–7. https://doi.org/10.1093/nar/gkaa892.CrossRefPubMed

21.

Zhou Y, Zhou B, Pache L, Chang M, Khodabakhshi A, Tanaseichuk O, Benner C, Chanda S. Metascape provides a biologist-oriented resource for the analysis of systems-level datasets. Nat Commun. 2019;10:1523. https://doi.org/10.1038/s41467-019-09234-6.ADSCrossRefPubMedPubMedCentral

22.

Kanehisa M, Furumichi M, Sato Y, Ishiguro-Watanabe M, Tanabe M. KEGG: integrating viruses and cellular organisms. Nucleic Acids Res. 2021;49:D545–51. https://doi.org/10.1093/nar/gkaa970.CrossRefPubMed

23.

Szklarczyk D, Gable A, Lyon D, Junge A, Wyder S, Huerta-Cepas J, Simonovic M, Doncheva N, Morris J, Bork P, et al. STRING v11: protein-protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets. Nucleic Acids Res. 2019;47:D607–13. https://doi.org/10.1093/nar/gky1131.CrossRefPubMed

24.

Tang Y, Li M, Wang J, Pan Y, Wu F. CytoNCA: a cytoscape plugin for centrality analysis and evaluation of protein interaction networks. Bio Syst. 2015;127:67–72. https://doi.org/10.1016/j.biosystems.2014.11.005.CrossRef

25.

Bittrich S, Rose Y, Segura J, Lowe R, Westbrook J, Duarte J, Burley S. Bioinf (Oxford England). 2022;38:1452–4. https://doi.org/10.1093/bioinformatics/btab813. RCSB Protein Data Bank: improved annotation, search and visualization of membrane protein structures archived in the PDB.

26.

Mao D, Jiang H, Zhang F, Yang H, Fang X, Zhang Q, Zhao G. HDAC2 exacerbates rheumatoid arthritis progression via the IL-17-CCL7 signaling pathway. Environ Toxicol. 2023;38:1743–55. https://doi.org/10.1002/tox.23802.ADSCrossRefPubMed

27.

Wang X, Tang K, Wang Y, Chen Y, Yang M, Gu C, Wang J, Wang Y, Yuan Y. Elevated microRNA–145–5p increases matrix metalloproteinase–9 by activating the nuclear factor–κB pathway in rheumatoid arthritis. Mol Med Rep. 2019;20:2703–11. https://doi.org/10.3892/mmr.2019.10499.CrossRefPubMedPubMedCentral

28.

Wei L, Liu M, Xiong H, Peng B. Up-regulation of IL-23 expression in human dental pulp fibroblasts by IL-17 via activation of the NF-κB and MAPK pathways. Int Endod J. 2018;51:622–31. https://doi.org/10.1111/iej.12871.CrossRefPubMed

29.

Sundrud M, Koralov S, Feuerer M, Calado D, Kozhaya A, Rhule-Smith A, Lefebvre R, Unutmaz D, Mazitschek R, Waldner H, et al. Halofuginone inhibits TH17 cell differentiation by activating the amino acid starvation response. Volume 324. New York, NY: Science; 2009. pp. 1334–8. https://doi.org/10.1126/science.1172638.CrossRef

30.

Luo L, Gao Y, Yang C, Shao Z, Wu X, Li S, Xiong L, Chen C. Halofuginone attenuates intervertebral discs degeneration by suppressing collagen I production and inactivating TGFβ and NF-кB pathway. Biomed Pharmacother. 2018;101:745–53. https://doi.org/10.1016/j.biopha.2018.01.100.CrossRefPubMed

31.

van den Noort M, de Boer M, Poolman B. Stability of ligand-induced protein conformation influences Affinity in Maltose-binding protein. J Mol Biol. 2021;433:167036. https://doi.org/10.1016/j.jmb.2021.167036.CrossRefPubMed

32.

Wang Y, Han C, Cui D, Li Y, Ma Y, Wei W. Is macrophage polarization important in rheumatoid arthritis? Int Immunopharmacol. 2017;50:345–52. https://doi.org/10.1016/j.intimp.2017.07.019.CrossRefPubMed

33.

Beringer A, Miossec P. Systemic effects of IL-17 in inflammatory arthritis. Nat Rev Rheumatol. 2019;15:491–501. https://doi.org/10.1038/s41584-019-0243-5.CrossRefPubMed

34.

Ito H, Yamada H, Shibata TN, Mitomi H, Nomoto S, Ozaki S. Dual role of interleukin-17 in pannus growth and osteoclastogenesis in rheumatoid arthritis. Arthritis Res Therapy. 2011;13:R14. https://doi.org/10.1186/ar3238.CrossRef

35.

Yamaguchi Y, Fujio K, Shoda H, Okamoto A, Tsuno NH, Takahashi K, Yamamoto K. IL-17B and IL-17 C are Associated with TNF-α production and contribute to the exacerbation of inflammatory arthritis. J Immunol. 2007;179:7128–36. https://doi.org/10.4049/jimmunol.179.10.7128.CrossRefPubMed

36.

Bian Y, Xiang Z, Wang Y, Ren Q, Chen G, Xiang B, Wang J, Zhang C, Pei S, Guo S, et al. Immunomodulatory roles of metalloproteinases in rheumatoid arthritis. Front Pharmacol. 2023;14:1–14. https://doi.org/10.3389/fphar.2023.1285455.CrossRef

37.

Sun H, Jiang Q, Fan W, Shen X, Wang Z, Wang X. TAGAP activates Th17 cell differentiation by promoting RhoA and NLRP3 to accelerate rheumatoid arthritis development. Clin Exp Immunol. 2023;214:26–35. https://doi.org/10.1093/cei/uxad084.CrossRefPubMed

38.

Luukkonen J, Huhtakangas J, Palosaari S, Tuukkanen J, Vuolteenaho O, Lehenkari P. Preliminary Report: Osteoarthritis and Rheumatoid Arthritis Synovial Fluid increased osteoclastogenesis in Vitro by Monocyte differentiation pathway regulating cytokines. Mediat Inflamm. 2022;2022(2606916). https://doi.org/10.1155/2022/2606916.

39.

Wu S, Zhou Y, Liu S, Zhang H, Luo H, Zuo X, Li T. Regulatory effect of nicotine on the differentiation of Th1, Th2 and Th17 lymphocyte subsets in patients with rheumatoid arthritis. Eur J Pharmacol. 2018;831:38–45. https://doi.org/10.1016/j.ejphar.2018.04.028.CrossRefPubMed

40.

Zhang Y, Lee T. Revealing the Immune heterogeneity between systemic Lupus Erythematosus and Rheumatoid Arthritis based on Multi-omics Data Analysis. Int J Mol Sci. 2022;23:5166. https://doi.org/10.3390/ijms23095166.CrossRefPubMedPubMedCentral

Title: Inhibition of IL-17 signaling in macrophages underlies the anti-arthritic effects of halofuginone hydrobromide: Network pharmacology, molecular docking, and experimental validation
Authors: Junping Zhu
Jiaming Wei
Ye Lin
Yuanyuan Tang
Zhaoli Su
Liqing Li
Bin Liu
Xiong Cai
Publication date: 01-12-2024
Publisher: BioMed Central
Keyword: Rheumatoid Arthritis
Published in: BMC Complementary Medicine and Therapies / Issue 1/2024
Electronic ISSN: 2662-7671
DOI: https://doi.org/10.1186/s12906-024-04397-2

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Inhibition of IL-17 signaling in macrophages underlies the anti-arthritic effects of halofuginone hydrobromide: Network pharmacology, molecular docking, and experimental validation

Abstract

Background

Methods

Results

Conclusion

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusion

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