Skip to main content

Advertisement

SpringerLink
Log in

Transcription factor EB promotes rheumatoid arthritis of Sprague–Dawley rats via regulating autophagy

  • Original Article
  • Published:
3 Biotech Aims and scope Submit manuscript

Abstract

This study investigated the effect of autophagy-related gene transcription factor EB (TFEB) on the rheumatoid arthritis (RA) and explored whether TFEB regulated RA by autophagy. The Sprague–Dawley rats were divided into two groups (n = 6). The rats were stimulated with the mixture of the type II collagen and Freund’s adjuvant or PBS at the root of the tail. Results showed that swollen and deformed joints were discovered, the levels of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) were elevated, and hematoxylin and eosin staining showed the inflammatory cells infiltrate the synovial tissue in the RA rats, compared to the control group. Immunohistochemistry displayed that the expressions of TFEB and LC3B increased in the synovial tissues of RA rats, whereas p62 decreased. The silence of TFEB in the RA-fibroblast-like synoviocytes (RA-FLS) decreased the protein expressions of LC3B, compared to the siRNA NC group. Meanwhile, the activity of FLS was raised, whereas the levels of TNF-α and IL-6 decreased in RA-FLS with TFEB knockdown. In conclusion, our study revealed that TFEB plays a crucial role in the progress of RA by regulating autophagy, which might provide novel targets for the therapy of RA.

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

Similar content being viewed by others

Data availability

All data and methods reported in the current study are accessed upon reasonable request.

References

  • Bao J, Chen Z, Xu L, Wu L, Xiong Y (2020) Rapamycin protects chondrocytes against IL-18-induced apoptosis and ameliorates rat osteoarthritis. Aging 12:5152–5167

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cao QH, Liu F, Yang ZL, Fu XH, Yang ZH, Liu Q, Wang L, Wan XB, Fan XJ (2016) Prognostic value of autophagy related proteins ULK1, Beclin 1, ATG3, ATG5, ATG7, ATG9, ATG10, ATG12, LC3B and p62/SQSTM1 in gastric cancer. Am J Transl Res 8:3831–3847

    CAS  PubMed  PubMed Central  Google Scholar 

  • Chadha S, Behl T, Bungau S, Kumar A, Kaur R, Venkatachalam T, Gupta A, Kandhwal M, Chandel D (2020) Focus on the multimodal role of autophagy in rheumatoid arthritis. Inflammation 44:1–12

    Article  PubMed  Google Scholar 

  • Choi AM, Ryter SW, Levine B (2013) Autophagy in human health and disease. N Engl J Med 368:651–662

    Article  CAS  PubMed  Google Scholar 

  • Chuang HC, Tan TH (2019) MAP4K3/GLK in autoimmune disease, cancer and aging. J Biomed Sci 26:82

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Chuang HC, Lan JL, Chen DY, Yang CY, Chen YM, Li JP, Huang CY, Liu PE, Wang X, Tan TH (2011) The kinase GLK controls autoimmunity and NF-kappaB signaling by activating the kinase PKC-theta in T cells. Nat Immunol 12:1113–1118

    Article  CAS  PubMed  Google Scholar 

  • Cortes CJ, La Spada AR (2019) TFEB dysregulation as a driver of autophagy dysfunction in neurodegenerative disease: molecular mechanisms, cellular processes, and emerging therapeutic opportunities. Neurobiol Dis 122:83–93

    Article  CAS  PubMed  Google Scholar 

  • Guo Q, Wang Y, Xu D, Nossent J, Pavlos NJ, Xu J (2018) Rheumatoid arthritis: pathological mechanisms and modern pharmacologic therapies. Bone Res 6:15

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • He Y, Xu Y, Zhang C, Gao X, Dykema KJ, Martin KR, Ke J, Hudson EA, Khoo SK, Resau JH et al (2011) Identification of a lysosomal pathway that modulates glucocorticoid signaling and the inflammatory response. Sci Signal 4:ra44

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Holers VM, Banda NK (2018) Complement in the initiation and evolution of rheumatoid arthritis. Front Immunol 9:1057

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Jannat A, John P, Bhatti A, Hayat MQ (2019) Tomorou attenuates progression of rheumatoid arthritis through alteration in ULK-1 independent autophagy pathway in collagen induced arthritis mice model. Cell Death Discov 5:142

    Article  PubMed  PubMed Central  Google Scholar 

  • Kato M, Ospelt C, Gay RE, Gay S, Klein K (2014) Dual role of autophagy in stress-induced cell death in rheumatoid arthritis synovial fibroblasts. Arthritis Rheumatol 66:40–48

    Article  CAS  PubMed  Google Scholar 

  • Kerlan-Candon S, Combe B, Vincent R, Clot J, Pinet V, Eliaou JF (2001) HLA-DRB1 gene transcripts in rheumatoid arthritis. Clin Exp Immunol 124:142–149

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Laha D, Deb M, Das H (2019) KLF2 (kruppel-like factor 2 [lung]) regulates osteoclastogenesis by modulating autophagy. Autophagy 15:2063–2075

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lauzier A, Charbonneau M, Harper K, Jilaveanu-Pelmus M, Dubois CM (2011) Formation of invadopodia-like structures by synovial cells promotes cartilage breakdown in collagen-induced arthritis: involvement of the protein tyrosine kinase Src. Arthritis Rheum 63:1591–1602

    Article  CAS  PubMed  Google Scholar 

  • Li S, Yu Y, Yue Y, Zhang Z, Su K (2013) Microbial infection and rheumatoid arthritis. J Clin Cell Immunol 4:174

    PubMed  PubMed Central  Google Scholar 

  • Li Z, Cui X, Lv H, Liu J, Di W, Jiang F, Liu Y, Cheng X (2020) Remote ischemic postconditioning attenuates damage in rats with chronic cerebral ischemia by upregulating the autophagolysosome pathway via the activation of TFEB. Exp Mol Pathol 115:104475

    Article  CAS  PubMed  Google Scholar 

  • Liu W, Li CC, Lu X, Bo LY, Jin FG (2019) Overexpression of transcription factor EB regulates mitochondrial autophagy to protect lipopolysaccharide-induced acute lung injury. Chin Med J 132:1298–1304

    Article  PubMed  PubMed Central  Google Scholar 

  • Liu Z, Chen D, Chen X, Bian F, Qin W, Gao N, Xiao Y, Li J, Pflugfelder SC, Li DQ (2020) Trehalose induces autophagy against inflammation by activating TFEB signaling pathway in human corneal epithelial cells exposed to hyperosmotic stress. Invest Ophthalmol Vis Sci 61:26

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ma X, Godar RJ, Liu H, Diwan A (2012) Enhancing lysosome biogenesis attenuates BNIP3-induced cardiomyocyte death. Autophagy 8:297–309

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Miana M, Galan M, Martinez-Martinez E, Varona S, Jurado-Lopez R, Bausa-Miranda B, Antequera A, Luaces M, Martinez-Gonzalez J, Rodriguez C et al (2015) The lysyl oxidase inhibitor beta-aminopropionitrile reduces body weight gain and improves the metabolic profile in diet-induced obesity in rats. Dis Model Mech 8:543–551

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mizushima N (2007) Autophagy: process and function. Genes Dev 21:2861–2873

    Article  CAS  PubMed  Google Scholar 

  • Mor A, Abramson SB, Pillinger MH (2005) The fibroblast-like synovial cell in rheumatoid arthritis: a key player in inflammation and joint destruction. Clin Immunol 115:118–128

    Article  CAS  PubMed  Google Scholar 

  • Nakamura S, Shigeyama S, Minami S, Shima T, Akayama S, Matsuda T, Esposito A, Napolitano G, Kuma A, Namba-Hamano T et al (2020) LC3 lipidation is essential for TFEB activation during the lysosomal damage response to kidney injury. Nat Cell Biol 22:1252–1263

    Article  CAS  PubMed  Google Scholar 

  • Narendra D, Tanaka A, Suen DF, Youle RJ (2008) Parkin is recruited selectively to impaired mitochondria and promotes their autophagy. J Cell Biol 183:795–803

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ni H, Xu S, Chen H, Dai Q (2020) Nicotine modulates CTSS (Cathepsin S) synthesis and secretion through regulating the autophagy-lysosomal machinery in atherosclerosis. Arterioscler Thromb Vasc Biol 40:2054–2069

    Article  CAS  PubMed  Google Scholar 

  • Palmieri M, Impey S, Kang H, di Ronza A, Pelz C, Sardiello M, Ballabio A (2011) Characterization of the CLEAR network reveals an integrated control of cellular clearance pathways. Hum Mol Genet 20:3852–3866

    Article  CAS  PubMed  Google Scholar 

  • Raben N, Puertollano R (2016) TFEB and TFE3: linking lysosomes to cellular adaptation to stress. Annu Rev Cell Dev Biol 32:255–278

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rajaei E, Mowla K, Ghorbani A, Bahadoram S, Bahadoram M, Dargahi-Malamir M (2015) The effect of omega-3 fatty acids in patients with active rheumatoid arthritis receiving DMARDs therapy: double-blind randomized controlled trial. Glob J Health Sci 8:18–25

    Article  PubMed  PubMed Central  Google Scholar 

  • Settembre C, Di Malta C, Polito VA, Garcia AM, Vetrini F, Erdin S, Erdin SU, Huynh T, Medina D, Colella P et al (2011) TFEB links autophagy to lysosomal biogenesis. Science 332:1429–1433

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sorice M, Iannuccelli C, Manganelli V, Capozzi A, Alessandri C, Lococo E, Garofalo T, Di Franco M, Bombardieri M, Nerviani A et al (2016) Autophagy generates citrullinated peptides in human synoviocytes: a possible trigger for anti-citrullinated peptide antibodies. Rheumatology 55:1374–1385

    Article  CAS  PubMed  Google Scholar 

  • Trivedi PC, Bartlett JJ, Mercer A, Slade L, Surette M, Ballabio A, Flibotte S, Hussein B, Rodrigues B, Kienesberger PC et al (2020) Loss of function of transcription factor EB remodels lipid metabolism and cell death pathways in the cardiomyocyte. Biochim Biophys Acta Mol Basis Dis 1866:165832

    Article  CAS  PubMed  Google Scholar 

  • Vomero M, Barbati C, Colasanti T, Perricone C, Novelli L, Ceccarelli F, Spinelli FR, Di Franco M, Conti F, Valesini G et al (2018) Autophagy and rheumatoid arthritis: current knowledges and future perspectives. Front Immunol 9:1577

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Wang L, Zhu B, Huang J, Xiang X, Tang Y, Ma L, Yan F, Cheng C, Qiu L (2020) Ultrasound-targeted microbubble destruction augmented synergistic therapy of rheumatoid arthritis via targeted liposomes. J Mater Chem B 8:5245–5256

    Article  CAS  PubMed  Google Scholar 

  • Wei W, Ren J, Yin W, Ding H, Lu Q, Tan L, Deng S, Liu J, Yang Q, Wang J et al (2020) Inhibition of Ctsk modulates periodontitis with arthritis via downregulation of TLR9 and autophagy. Cell Prolif 53:e12722

    Article  PubMed  Google Scholar 

  • Weiskirchen R, Tacke F (2019) Relevance of autophagy in parenchymal and non-parenchymal liver cells for health and disease. Cells 8:16

    Article  CAS  PubMed Central  Google Scholar 

  • Xu K, Xu P, Yao JF, Zhang YG, Hou WK, Lu SM (2013) Reduced apoptosis correlates with enhanced autophagy in synovial tissues of rheumatoid arthritis. Inflamm Res 62:229–237

    Article  CAS  PubMed  Google Scholar 

  • Xu K, Cai YS, Lu SM, Li XL, Liu L, Li Z, Liu H, Xu P (2015) Autophagy induction contributes to the resistance to methotrexate treatment in rheumatoid arthritis fibroblast-like synovial cells through high mobility group box chromosomal protein 1. Arthritis Res Ther 17:374

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Yang R, Zhang Y, Wang L, Hu J, Wen J, Xue L, Tang M, Liu Z, Fu J (2017) Increased autophagy in fibroblast-like synoviocytes leads to immune enhancement potential in rheumatoid arthritis. Oncotarget 8:15420–15430

    Article  PubMed  Google Scholar 

  • Yu C, Li M, Duan X, Fang Y, Li Q, Wu R, Liu S, Wang Y, Wu Z, Shi X et al (2018) Chinese registry of rheumatoid arthritis (CREDIT): I. Introduction and prevalence of remission in Chinese patients with rheumatoid arthritis. Clin Exp Rheumatol 36:836–840

    PubMed  Google Scholar 

  • Zheng G, Zhan Y, Li X, Pan Z, Zheng F, Zhang Z, Zhou Y, Wu Y, Wang X, Gao W et al (2018) TFEB, a potential therapeutic target for osteoarthritis via autophagy regulation. Cell Death Dis 9:858

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Zhou DM, Ran F, Ni HZ, Sun LL, Xiao L, Li XQ, Li WD (2020a) Metformin inhibits high glucose-induced smooth muscle cell proliferation and migration. Aging 12:5352–5361

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhou W, Shen Q, Wang H, Yang J, Zhang C, Deng Z, Wu K, Zhou Y, Zeng J, Zhang Y et al (2020b) Knockdown of YAP/TAZ inhibits the migration and invasion of fibroblast synovial cells in rheumatoid arthritis by regulating autophagy. J Immunol Res 2020:9510594

    Article  PubMed  PubMed Central  Google Scholar 

  • Zhu L, Wang H, Wu Y, He Z, Qin Y, Shen Q (2017) The autophagy level is increased in the synovial tissues of patients with active rheumatoid arthritis and is correlated with disease severity. Mediators Inflamm 2017:7623145

    Article  PubMed  PubMed Central  CAS  Google Scholar 

Download references

Funding

This work is supported by the Natural Science Foundation of the Jiangsu Higher Education Institutions of China (19KJB310016), Suzhou Science Foundation (SYSD2019181), the Second Affiliated Hospital of Soochow University Science Foundation (SDFEYQN1720). We thank all the researchers involved in this project.

Author information

Authors and Affiliations

  1. Department of Pharmacy, the Second Affiliated Hospital of Soochow University, No 1055, Sanxiang Road, Gusu District, Suzhou, 215004, Jiangsu, China

    De Lai Xu & Jie Pan

Authors
  1. De Lai Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jie Pan
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

DLX finished the experiment and wrote the manuscript. JP designed the experiment and revised the manuscript. The authors agree to publish this paper.

Corresponding author

Correspondence to Jie Pan.

Ethics declarations

Conflict of interest

All authors declared that there was no conflict of interest.

Ethical approval

The authors declare that all of the actions were following the ethical requirements, including plagiarism, data fabrication and/or falsification, misconduct, double publication and/or submission, and so on.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Xu, D.L., Pan, J. Transcription factor EB promotes rheumatoid arthritis of Sprague–Dawley rats via regulating autophagy. 3 Biotech 11, 162 (2021). https://doi.org/10.1007/s13205-021-02710-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s13205-021-02710-1

Keywords

Search

Navigation