Skip to main content

Advertisement

SpringerLink
Log in

Morin, the PPARγ agonist, inhibits Th17 differentiation by limiting fatty acid synthesis in collagen-induced arthritis

  • Original Article
  • Published:
Cell Biology and Toxicology Aims and scope Submit manuscript

Abstract

T helper (Th) 17 cells highly contribute to the immunopathology of rheumatoid arthritis. Morin, a natural flavonoid, owns well anti-arthritic action but unclear effect on Th17 differentiation. This study tried to solve this issue and explore the mechanisms in view of cellular metabolism. Naïve CD4+ T cells were treated with anti-CD3/CD28 along with Th17-inducing cytokines. Morin was shown to block Th17 differentiation without affecting cell viability even when Foxp3 was dampened. The mechanisms were ascribed to the limited fatty acid synthesis by restricting FASN transcription, as indicated by metabolomics analysis, nile red staining, detection of triglycerides, FASN overexpression, and addition of palmitic acid. Moreover, morin had slight effect on cell apoptosis and protein palmitoylation during Th17 differentiation, but blocked the binding of RORγt to promoter and CNS2 region of Il17a gene. Oleic acid rescued the inhibition of morin on RORγt function, and Th17-inducing cytokines could not induce RORγt function in SCD1-defficient cells, suggesting that oleic acid but not palmitic acid was the direct effector in the action of morin. Then, PPARγ was identified as the target of morin, and GW9662 or PPARγ CRISPR/Cas9 KO plasmid weakened its above-mentioned effects. The transrepression of FASN by morin was owing to physical interaction between PPARγ and Sp1, and the importance of Sp1 in Th17 differentiation was confirmed by siSp1. Finally, the effects and mechanisms for morin-dampened Th17 responses were confirmed in collagen-induced arthritis (CIA) mice. Collectively, morin inhibited Th17 differentiation and alleviated CIA by limiting fatty acid synthesis subsequent to PPARγ activation.

Graphical abstract

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

Data availability

All data generated or analyzed during this study are included in this published article.

Code availability

Not applicable.

References

  • Augimeri G, Giordano C, Gelsomino L, Plastina P, Barone I, Catalano S, et al. The role of PPARγ ligands in breast cancer: from basic research to clinical studies. Cancers (Basel). 2020;12:2623.

    Article  CAS  PubMed  Google Scholar 

  • Berod L, Friedrich C, Nandan A, Freitag J, Hagemann S, Harmrolfs K, et al. De novo fatty acid synthesis controls the fate between regulatory T and T helper 17 cells. Nat Med. 2014;20:1327–33.

    Article  CAS  PubMed  Google Scholar 

  • Bieerkehazhi S, Fan Y, West SJ, Tewari R, Ko J, Mills T, et al. Ca2+-dependent protein acyltransferase DHHC21 controls activation of CD4+ T cells. J Cell Sci. 2022;135:jcs258186.

    Article  CAS  PubMed  Google Scholar 

  • Carvalho MV, Gonçalves-de-Albuquerque CF, Silva AR. PPAR gamma: from definition to molecular targets and therapy of lung diseases. Int J Mol Sci. 2021;22:805.

    Article  PubMed  PubMed Central  Google Scholar 

  • Cheng HS, Yip YS, Lim EKY, Wahli W, Tan NS. PPARs and tumor microenvironment: the emerging roles of the metabolic master regulators in tumor stromal-epithelial crosstalk and carcinogenesis. Cancers (Basel). 2021;13:2153.

    Article  CAS  PubMed  Google Scholar 

  • Cheng Y, Jia B, Wang Y, Wan S. miR-133b acts as a tumor suppressor and negatively regulates ATP citrate lyase via PPARγ in gastric cancer. Oncol Rep. 2017;38:3220–6.

    Article  CAS  PubMed  Google Scholar 

  • Dhanasekar C, Rasool M. Morin, a dietary bioflavonol suppresses monosodium urate crystal-induced inflammation in an animal model of acute gouty arthritis with reference to NLRP3 inflammasome, hypo-xanthine phospho-ribosyl transferase, and inflammatory mediators. Eur J Pharmacol. 2016;786:116–27.

    Article  CAS  PubMed  Google Scholar 

  • Endo Y, Asou HK, Matsugae N, Hirahara K, Shinoda K, Tumes DJ, et al. Obesity drives Th17 cell differentiation by inducing the lipid metabolic kinase, ACC1. Cell Rep. 2015;12:1042–55.

    Article  CAS  PubMed  Google Scholar 

  • Garcia Corrales AV, Haidar M, Bogie JFJ, Hendriks JJA. Fatty acid synthesis in glial cells of the CNS. Int J Mol Sci. 2021;22:8159.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Glass CK, Saijo K. Nuclear receptor transrepression pathways that regulate inflammation in macrophages and T cells. Nat Rev Immunol. 2010;10:365–76.

    Article  CAS  PubMed  Google Scholar 

  • Hasan M, Neumann B, Haupeltshofer S, Stahlke S, Fantini MC, Angstwurm K, et al. Activation of TGF-β-induced non-Smad signaling pathways during Th17 differentiation. Immunol Cell Biol. 2015;93:662–72.

    Article  CAS  PubMed  Google Scholar 

  • Hasan Z, Koizumi SI, Sasaki D, Yamada H, Arakaki N, Fujihara Y, et al. JunB is essential for IL-23-dependent pathogenicity of Th17 cells. Nat Commun. 2017;8:15628.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Huang J, Xu X, Yang J. MiRNAs alter T helper 17 cell fate in the pathogenesis of autoimmune diseases. Front Immunol. 2021;12: 593473.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Klotz L, Burgdorf S, Dani I, Saijo K, Flossdorf J, Hucke S, et al. The nuclear receptor PPAR gamma selectively inhibits Th17 differentiation in a T cell-intrinsic fashion and suppresses CNS autoimmunity. J Exp Med. 2009;206:2079–89.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kono M, Yoshida N, Maeda K, Tsokos GC. Transcriptional factor ICER promotes glutaminolysis and the generation of Th17 cells. Proc Natl Acad Sci U S A. 2018;115:2478–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lee BH, Hsu WH, Huang T, Chang YY, Hsu YW, Pan TM. Monascin improves diabetes and dyslipidemia by regulating PPARγ and inhibiting lipogenesis in fructose-rich diet-induced C57BL/6 mice. Food Funct. 2013;4:950–9.

    Article  CAS  PubMed  Google Scholar 

  • Liu Y, Wang J, Luo S, Zhan Y, Lu Q. The roles of PPARγ and its agonists in autoimmune diseases: a comprehensive review. J Autoimmun. 2020;113: 102510.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lu S, Archer MC. Sp1 coordinately regulates de novo lipogenesis and proliferation in cancer cells. Int J Cancer. 2010;126:416–25.

    Article  CAS  PubMed  Google Scholar 

  • Madan Kumar P, Naveen Kumar P, Devaraj H, Niranjali DS. Morin, a dietary flavonoid, exhibits anti-fibrotic effect and induces apoptosis of activated hepatic stellate cells by suppressing canonical NF-κB signaling. Biochimie. 2015;110:107–18.

    Article  CAS  PubMed  Google Scholar 

  • Matsuo S, Yang WL, Aziz M, Kameoka S, Wang P. Fatty acid synthase inhibitor C75 ameliorates experimental colitis. Mol Med. 2014;20:1–9.

    Article  PubMed  Google Scholar 

  • Miao Y, Geng Y, Yang L, Zheng Y, Dai Y, Wei Z. Morin inhibits the transformation of fibroblasts towards myofibroblasts through regulating “PPAR-γ-glutaminolysis-DEPTOR” pathway in pulmonary fibrosis. J Nutr Biochem. 2021a;101: 108923.

    Article  PubMed  Google Scholar 

  • Miao Y, Zheng Y, Geng Y, Yang L, Cao N, Dai Y, et al. The role of GLS1-mediated glutaminolysis/2-HG/H3K4me3 and GSH/ROS signals in Th17 responses counteracted by PPARγ agonists. Theranostics. 2021b;11:4531–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Necela BM, Su W, Thompson EA. Peroxisome proliferator-activated receptor gamma down-regulates follistatin in intestinal epithelial cells through SP1. J Biol Chem. 2008;283:29784–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Park HJ, Park HS, Lee JU, Bothwell AL, Choi JM. Sex-based selectivity of PPARγ regulation in Th1, Th2, and Th17 differentiation. Int J Mol Sci. 2016;17:1347.

    Article  PubMed  PubMed Central  Google Scholar 

  • Shen H, Shi LZ. Metabolic regulation of TH17 cells. Mol Immunol. 2019;109:81–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shi LZ, Wang R, Huang G, Vogel P, Neale G, Green DR, et al. HIF1alpha-dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of TH17 and Treg cells. J Exp Med. 2011;208:1367–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sugawara A, Uruno A, Kudo M, Ikeda Y, Sato K, Taniyama Y, et al. Transcription suppression of thromboxane receptor gene by peroxisome proliferator-activated receptor-gamma via an interaction with Sp1 in vascular smooth muscle cells. J Biol Chem. 2002;277:9676–83.

    Article  CAS  PubMed  Google Scholar 

  • Sun L, Fu J, Zhou Y. Metabolism controls the balance of Th17/T-regulatory cells. Front Immunol. 2017;8:1632.

    Article  PubMed  PubMed Central  Google Scholar 

  • Tang KT, Lin CC, Lin SC, Wang JH, Tsai SW. Kurarinone attenuates collagen-induced arthritis in mice by inhibiting Th1/Th17 cell responses and oxidative stress. Int J Mol Sci. 2021;22:4002.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ventura R, Mordec K, Waszczuk J, Wang Z, Lai J, Fridlib M, et al. Inhibition of de novo palmitate synthesis by fatty acid synthase induces apoptosis in tumor cells by remodeling cell membranes, inhibiting signaling pathways, and reprogramming gene expression. EBioMedicine. 2015;2:808–24.

    Article  PubMed  PubMed Central  Google Scholar 

  • Wan J, Roth AF, Bailey AO, Davis NG. Palmitoylated proteins: purification and identification. Nat Protoc. 2007;2:1573–84.

    Article  CAS  PubMed  Google Scholar 

  • Wang G, Su Z, Li H, Xiao L, Li C, Lian G. The role of metabolism in Th17 cell differentiation and autoimmune diseases. Int Immunopharmacol. 2021;103: 108450.

    Article  PubMed  Google Scholar 

  • Wolf SS, Roder KH, Schweizer M. The general transcription factor Sp1 plays an important role in the regulation of fatty acid synthase. Biochem Soc Trans. 1998;26:S95.

    Article  CAS  PubMed  Google Scholar 

  • Wu B, Wan Y. Molecular control of pathogenic Th17 cells in autoimmune diseases. Int Immunopharmacol. 2020;80: 106187.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Xin W, Huang C, Zhang X, Xin S, Zhou Y, Ma X, et al. Methyl salicylate lactoside inhibits inflammatory response of fibroblast-like synoviocytes and joint destruction in collagen-induced arthritis in mice. Br J Pharmacol. 2014;171:3526–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Xu T, Stewart KM, Wang X, Liu K, Xie M, Ryu JK, et al. Metabolic control of TH17 and induced Treg cell balance by an epigenetic mechanism. Nature. 2017;548:228–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yang H, Liu Y, Zhao MM, Guo Q, Zheng XK, Liu D, et al. Therapeutic potential of targeting membrane-spanning proteoglycan SDC4 in hepatocellular carcinoma. Cell Death Dis. 2021;12:492.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yang J, Sundrud MS, Skepner J, Yamagata T. Targeting Th17 cells in autoimmune diseases. Trends Pharmacol Sci. 2014;35:493–500.

    Article  CAS  PubMed  Google Scholar 

  • Yang P, Qian FY, Zhang MF, Xu AL, Wang X, Jiang BP, et al. Th17 cell pathogenicity and plasticity in rheumatoid arthritis. J Leukoc Biol. 2019;106:1233–40.

    Article  CAS  PubMed  Google Scholar 

  • Yang P, Zhang M, Wang X, Xu AL, Shen M, Jiang B, et al. MicroRNA let-7g-5p alleviates murine collagen-induced arthritis by inhibiting Th17 cell differentiation. Biochem Pharmacol. 2020a;174: 113822.

    Article  CAS  PubMed  Google Scholar 

  • Yang X, Chatterjee V, Ma Y, Zheng E, Yuan SY. Protein palmitoylation in leukocyte signaling and function. Front Cell Dev Biol. 2020b;8: 600368.

    Article  PubMed  PubMed Central  Google Scholar 

  • Young KE, Flaherty S, Woodman KM, Sharma-Walia N, Reynolds JM. Fatty acid synthase regulates the pathogenicity of Th17 cells. J Leukoc Biol. 2017;102:1229–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yue M, Tao Y, Fang Y, Lian X, Zhang Q, Xia Y, et al. The gut microbiota modulator berberine ameliorates collagen-induced arthritis in rats by facilitating the generation of butyrate and adjusting the intestinal hypoxia and nitrate supply. FASEB J. 2019;33:12311–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yue M, Zeng N, Xia Y, Wei Z, Dai Y. Morin exerts anti-arthritic effects by attenuating synovial angiogenesis via activation of peroxisome proliferator activated receptor-γ. Mol Nutr Food Res. 2018;62: e1800202.

    Article  PubMed  Google Scholar 

  • Yun SH, Shin SW, Park JI. Expression of fatty acid synthase is regulated by PGC-1α and contributes to increased cell proliferation. Oncol Rep. 2017;38:3497–506.

    CAS  PubMed  Google Scholar 

  • Zhang M, Zhou L, Xu Y, Yang M, Xu Y, Komaniecki GP, et al. A STAT3 palmitoylation cycle promotes TH17 differentiation and colitis. Nature. 2020;586:434–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang Q, Fang Y, Lv C, Zhu Y, Xia Y, Wei Z, et al. Norisoboldine induces the development of Treg cells by promoting fatty acid oxidation-mediated H3K27 acetylation of Foxp3. FASEB J. 2022;36: e22230.

    CAS  PubMed  Google Scholar 

Download references

Funding

This work was supported by the National Natural Science Foundation of China (81773970), Qing Lan Project of Jiangsu Province (2019), the “Double First-Class” University Project (CPU2018GY10), the University Innovation Research and Training Program of China Pharmaceutical University (202110316068), and partially supported by the Priority Academic Program Development of Jiangsu Higher Education Institutions.

Author information

Author notes

  1. Yumeng Miao and Xiaoqian Wu equally contributed to this paper.

Authors and Affiliations

  1. Department of Pharmacology of Chinese Materia Medica, School of Traditional Chinese Pharmacy, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing, 210009, China

    Yumeng Miao, Xiaoqian Wu, Xinru Xue, Xingyu Ma, Ling Yang, Xi Zeng, Yuxiao Hu, Yue Dai & Zhifeng Wei

Authors
  1. Yumeng Miao
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xiaoqian Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xinru Xue
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Xingyu Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ling Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Xi Zeng
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yuxiao Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yue Dai
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Zhifeng Wei
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Zhifeng Wei and Yue Dai designed the study. Yumeng Miao, Xiaoqian Wu, Xinru Xue, Xingyu Ma, Ling Yang, Xi Zeng, and Yuxiao Hu performed the experiments and statistical analysis. Yumeng Miao additionally contributed to the preparation of the manuscript. All of the authors approved the final version of this manuscript.

Corresponding authors

Correspondence to Yue Dai or Zhifeng Wei.

Ethics declarations

Ethics approval

This study was approved by the Animal Ethics Committee of China Pharmaceutical University and followed the National Institute of Health guidelines on the ethical use of animals.

Consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.

Additional information

Publisher's note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Graphical headlights

1. Morin limits Th17 differentiation by restricting FASN-mediated fatty acid synthesis

2. Morin dampens RORγt function subsequent to the restriction of fatty acid synthesis

3. Morin inhibits FASN transcription via PPARγ-Sp1 signaling

4. Morin carries out anti-arthritic action through limiting Th17 responses

Rights and permissions

Springer Nature or its licensor 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

Miao, Y., Wu, X., Xue, X. et al. Morin, the PPARγ agonist, inhibits Th17 differentiation by limiting fatty acid synthesis in collagen-induced arthritis. Cell Biol Toxicol 39, 1433–1452 (2023). https://doi.org/10.1007/s10565-022-09769-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10565-022-09769-3

Keywords

Search

Navigation