SpringerLink
Log in

Liver X receptor inverse agonist SR9243 attenuates rheumatoid arthritis via modulating glycolytic metabolism of macrophages

  • Article
  • Published:
Acta Pharmacologica Sinica Submit manuscript

Abstract

Liver X receptors (LXRs) which link lipid metabolism and inflammation, were overexpressed in experimental rheumatoid arthritis (RA) rats as observed in our previous studies, while suppression of LXRα by silybin ameliorates arthritis and abnormal lipid metabolism. However, the role of LXRs in RA remains undefined. In this study, we investigated the inhibition role of LXRs in the polarization and activation of M1 macrophage by using a special LXRs inverse agonist SR9243, which led to ameliorating the progression of adjuvant-induced arthritis (AIA) in rats. Mechanistically, SR9243 disrupted the LPS/IFN-γ-induced Warburg effect in M1 macrophages, while glycolysis inhibitor 2-DG attenuated the inhibition effect of SR9243 on M1 polarization and the cytokines expression of M1 macrophages including iNOS, TNF-α, and IL-6 in vitro. Furthermore, SR9243 downregulated key glycolytic enzymes, including LDH-A, HK2, G6PD, GLUT1, and HIF-1α in M1 macrophages, which is mediated by increased phosphorylation of AMPK (Thr172) and reduced downstream phosphorylation of mTOR (Ser2448). Importantly, gene silencing of LXRs compromises the inhibition effect of SR9243 on M1 macrophage polarization and activation. Collectively, for the first time, our findings suggest that the LXR inverse agonist SR9243 mitigates adjuvant-induced rheumatoid arthritis and protects against bone erosion by inhibiting M1 macrophage polarization and activation through modulation of glycolytic metabolism via the AMPK/mTOR/HIF-1α pathway.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price includes VAT (France)

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1: A marked augmentation in the expression of NR1H3 (LXRα) within the synovial tissue of RA samples.
Fig. 2: SR9243 ameliorates arthritis progression in AIA rats and decreases M1 macrophages in synovium.
Fig. 3: Effects of SR9243 on M1 macrophage polarization and pro-inflammation function in vitro.
Fig. 4: SR9243 disrupts LPS/IFN-γ-induced Warburg effect in M1 macrophages.
Fig. 5: SR9243 inhibits the expression of glycolytic enzyme genes in M1 macrophages.
Fig. 6: SR9243 inhibits M1 macrophage polarization and function via the AMPK and mTOR pathway.
Fig. 7: Silence of LXR abrogates the inhibition effects of SR9243 in M1 macrophage polarization.

References

  1. McInnes IB, Schett G. The pathogenesis of rheumatoid arthritis. N Engl J Med. 2011;365:2205–19.

    Article  CAS  PubMed  Google Scholar 

  2. Aletaha D, Smolen JS. Diagnosis and management of rheumatoid arthritis: a review. JAMA. 2018;320:1360–72.

    Article  PubMed  Google Scholar 

  3. Kinne RW, Bräuer R, Stuhlmüller B, Palombo-Kinne E, Burmester GR. Macrophages in rheumatoid arthritis. Arthritis Res. 2000;2:189–202.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Xu Y, Zhang Z, He J, Chen Z. Immune effects of macrophages in rheumatoid arthritis: a bibliometric analysis from 2000 to 2021. Front Immunol. 2022;13:903771.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Yang X, Chang Y, Wei W. Emerging role of targeting macrophages in rheumatoid arthritis: Focus on polarization, metabolism and apoptosis. Cell Prolif. 2020;53:12854.

    Article  Google Scholar 

  6. Liu Y, Xu R, Gu H, Zhang E, Qu J, Cao W, et al. Metabolic reprogramming in macrophage responses. Biomark Res. 2021;9:1.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Yu Q, Wang Y, Dong L, He Y, Liu R, Yang Q, et al. Regulations of glycolytic activities on macrophages functions in tumor and infectious inflammation. Front Cell Infect Microbiol. 2020;10:287.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Bae S, Park PSU, Lee Y, Mun SH, Giannopoulou E, Fujii T, et al. MYC-mediated early glycolysis negatively regulates proinflammatory responses by controlling IRF4 in inflammatory macrophages. Cell Rep. 2021;35:109264.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. **e Y, Feng SL, Mai CT, Zheng YF, Wang H, Liu ZQ, et al. Suppression of up-regulated LXRα by silybin ameliorates experimental rheumatoid arthritis and abnormal lipid metabolism. Phytomedicine: Int J Phytother Phytopharmacol. 2021;80:153339.

    Article  CAS  Google Scholar 

  10. Asquith DL, Ballantine LE, Nijjar JS, Makdasy MK, Patel S, Wright PB, et al. The liver X receptor pathway is highly upregulated in rheumatoid arthritis synovial macrophages and potentiates TLR-driven cytokine release. Ann Rheum Dis. 2013;72:2024–31.

    Article  CAS  PubMed  Google Scholar 

  11. Aleja AG, Herrero C, Torres-Torresano M, Schiaffino MT, Del Castillo A, Alonso B, et al. Inhibition of LXR controls the polarization of human inflammatory macrophages through upregulation of MAFB. Cell Mol Life Sci. 2023;80:96.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Ménégaut L, Jalil A, Pilot T, Dongen K, Crespy V, Steinmetz E, et al. Regulation of glycolytic genes in human macrophages by oxysterols: a potential role for liver X receptors. Br J Pharmacol. 2021;178:3124–39.

    Article  PubMed  Google Scholar 

  13. Repa JJ, Mangelsdorf DJ. The role of orphan nuclear receptors in the regulation of cholesterol homeostasis. Annu Rev Cell Dev Biol. 2000;16:459–81.

    Article  CAS  PubMed  Google Scholar 

  14. Flaveny CA, Griffett K, El-Gendy Bel D, Kazantzis M, Sengupta M, Amelio AL, et al. Broad anti-tumor activity of a small molecule that selectively targets the Warburg effect and lipogenesis. Cancer Cell. 2015;28:42–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Inglis JJ, Criado G, Medghalchi M, Andrews M, Sandison A, Feldmann M, et al. Collagen-induced arthritis in C57BL/6 mice is associated with a robust and sustained T-cell response to type II collagen. Arthritis Res Ther. 2007;9:113.

    Article  Google Scholar 

  16. Qu B, Wang XL, Zheng DC, Mai CT, Liu ZQ, Zhou H, et al. Novel treatment for refractory rheumatoid arthritis with total glucosides of paeony and nobiletin codelivered in a self-nanoemulsifying drug delivery system. Acta Pharmacol Sin. 2022;43:2094–108.

    Article  CAS  PubMed  Google Scholar 

  17. Zheng D, Liu Z, Zhou Y, Hou N, Yan W, Qin Y, et al. Urolithin B, a gut microbiota metabolite, protects against myocardial ischemia/reperfusion injury via p62/Keap1/Nrf2 signaling pathway. Pharmacol Res. 2020;153:104655.

    Article  CAS  PubMed  Google Scholar 

  18. Luise M, Sollazzo M, Lama E, Coadă CA, Bressi L, Iorio M, et al. Inducing respiratory complex I impairment elicits an increase in PGC1α in ovarian cancer. Sci Rep. 2022;12:8020.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Zhang F, Wei K, Slowikowski K, Fonseka CY, Rao DA, Kelly S, et al. Defining inflammatory cell states in rheumatoid arthritis joint synovial tissues by integrating single-cell transcriptomics and mass cytometry. Nat Immunol. 2019;20:928–42.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Alten R, Gram H, Joosten LA, Berg WB, Sieper J, Wassenberg S, et al. The human anti-IL-1 beta monoclonal antibody ACZ885 is effective in joint inflammation models in mice and in a proof-of-concept study in patients with rheumatoid arthritis. Arthritis Res Ther. 2008;10:67.

    Article  Google Scholar 

  21. Alten R, Gomez-Reino J, Durez P, Beaulieu A, Sebba A, Krammer G, et al. Efficacy and safety of the human anti-IL-1β monoclonal antibody canakinumab in rheumatoid arthritis: results of a 12-week, Phase II, dose-finding study. BMC Musculoskelet Disord. 2011;12:153.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Siebert S, Tsoukas A, Robertson J, McInnes I. Cytokines as therapeutic targets in rheumatoid arthritis and other inflammatory diseases. Pharmacol Rev. 2015;67:280–309.

    Article  CAS  PubMed  Google Scholar 

  23. Cai W, Cheng J, Zong S, Yu Y, Wang Y, Song Y, et al. The glycolysis inhibitor 2-deoxyglucose ameliorates adjuvant-induced arthritis by regulating macrophage polarization in an AMPK-dependent manner. Mol Immunol. 2021;140:186–95.

    Article  CAS  PubMed  Google Scholar 

  24. Byles V, Covarrubias AJ, Ben-Sahra I, Lamming DW, Sabatini DM, Manning BD, et al. The TSC-mTOR pathway regulates macrophage polarization. Nat Commun. 2013;4:2834.

    Article  PubMed  Google Scholar 

  25. Kelly B, O’Neill LA. Metabolic reprogramming in macrophages and dendritic cells in innate immunity. Cell Res. 2015;25:771–84.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Savla SR, Prabhavalkar KS, Bhatt LK. Liver X receptor: a potential target in the treatment of atherosclerosis. Expert Opin Ther Targets. 2022;26:645–58.

    Article  CAS  PubMed  Google Scholar 

  27. Li N, Li Y, Han X, Zhang J, Han J, Jiang X, et al. LXR agonist inhibits inflammation through regulating MyD88 mRNA alternative splicing. Front Pharmacol. 2022;13:973612.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Im SS, Osborne TF. Liver x receptors in atherosclerosis and inflammation. Circ Res. 2011;108:996–1001.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Thomas DG, Doran AC, Fotakis P, Westerterp M, Antonson P, Jiang H, et al. LXR suppresses inflammatory gene expression and neutrophil migration through cis-repression and cholesterol efflux. Cell Rep. 2018;25:3774–85.e4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Griffett K, Solt LA, El-Gendy B-D, Kamenecka TM, Burris TP. A liver-selective LXR inverse agonist that suppresses hepatic steatosis. ACS Chem Biol. 2013;8:559–67.

    Article  CAS  PubMed  Google Scholar 

  31. Griffett K, Welch RD, Flaveny CA, Kolar GR, Neuschwander-Tetri BA, Burris TP. The LXR inverse agonist SR9238 suppresses fibrosis in a model of non-alcoholic steatohepatitis. Mol Metab. 2015;4:353–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Huang P, Kaluba B, Jiang XL, Chang S, Tang XF, Mao LF, et al. Liver X receptor inverse agonist SR9243 suppresses nonalcoholic steatohepatitis intrahepatic inflammation and fibrosis. BioMed Res Int. 2018: 807:1093.

  33. Russell DG, Huang L, VanderVen BC. Immunometabolism at the interface between macrophages and pathogens. Nat Rev Immunol. 2019;19:291–304.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Cheng SC, Quintin J, Cramer RA, Shepardson KM, Saeed S, Kumar V, et al. mTOR- and HIF-1α-mediated aerobic glycolysis as metabolic basis for trained immunity. Science. 2014;345:1250684.

  35. Faubert B, Boily G, Izreig S, Griss T, Samborska B, Dong Z, et al. AMPK is a negative regulator of the Warburg effect and suppresses tumor growth in vivo. Cell Metab. 2013;17:113–24.

    Article  CAS  PubMed  Google Scholar 

  36. Herzig S, Shaw RJ. AMPK: guardian of metabolism and mitochondrial homeostasis. Nat Rev Mol Cell Biol. 2018;19:121–35.

    Article  CAS  PubMed  Google Scholar 

  37. Rodríguez C, Muñoz M, Contreras C, Prieto D. AMPK, metabolism, and vascular function. FEBS J. 2021;288:3746–71.

    Article  PubMed  Google Scholar 

  38. Kanagaki S, Tsutsui Y, Kobayashi N, Komine T, Ito M, Akasaka Y, et al. Activation of AMP-activated protein kinase (AMPK) through inhibiting interaction with prohibitins. iScience. 2023;26:106293.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Fullerton MD, Ford RJ, McGregor CP, LeBlond ND, Snider SA, Stypa SA, et al. Salicylate improves macrophage cholesterol homeostasis via activation of Ampk. J Lipid Res. 2015;56:1025–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Yu SCY, Jiang P, Peng W, Cheng SH, Cheung YTT, Tse OYO, et al. Single-molecule sequencing reveals a large population of long cell-free DNA molecules in maternal plasma. Proc Natl Acad Sci USA. 2021;118:e2114937118.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Goel D, Vohora D. Liver X receptors and skeleton: Current state-of-knowledge. Bone. 2021;144:115807.

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

This work was funded by the State Key Laboratory of Dampness Syndrome of Chinese Medicine in the Second Affiliated Hospital of Guangzhou University of Chinese Medicine (File no. SZ2022KF08), and the Science and Technology Development Fund, Macau SAR (File no. 0075/2019/AMJ).

Author information

Author notes

  1. These authors contributed equally: De-chong Zheng, Jia-qin Hu

Authors and Affiliations

  1. State Key Laboratory of Traditional Chinese Medicine Syndrome, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, 510006, China

    De-chong Zheng, Jia-qin Hu, Li Huang, Hua Zhou & Ying **e

  2. State Key Laboratory of Quality Research in Chinese Medicines, Macau University of Science and Technology, Macau, China

    De-chong Zheng, Jia-qin Hu, Chu-tian Mai & Li-li Yu

Authors
  1. De-chong Zheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jia-qin Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Chu-tian Mai
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Li Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hua Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Li-li Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ying **e
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

DCZ, JQH, and YX conceived and designed the experiments. DCZ and JQH wrote the manuscript. HZ and YX corrected the draft. YX and LLY supervised the experimentation. DCZ, JQH, CTM, and LH carried out the experiments and analyzed the data. All data were generated in-house, and no paper mill was used. All authors agree to be accountable for all aspects of work ensuring integrity and accuracy.

Corresponding authors

Correspondence to Li-li Yu or Ying **e.

Ethics declarations

Competing interests

The authors declare no competing interests.

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zheng, Dc., Hu, Jq., Mai, Ct. et al. Liver X receptor inverse agonist SR9243 attenuates rheumatoid arthritis via modulating glycolytic metabolism of macrophages. Acta Pharmacol Sin (2024). https://doi.org/10.1038/s41401-024-01315-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1038/s41401-024-01315-7

  • Springer Nature Singapore Pte Ltd.

Keywords

Search

Navigation