Intervening Upregulated SLC7A5 Could Mitigate Inflammatory Mediator by MTOR-P70S6K Signal in Rheumatoid Arthritis Synoviocytes

Overview

Journal Arthritis Res Ther

Publisher Biomed Central

Specialty Rheumatology

Date 2020 Sep 2

PMID 32867828

Citations 14

Authors

Jing Xu

Congshan Jiang

Yongsong Cai

Yuanxu Guo

Xipeng Wang

Jiaxiang Zhang

Jiawen Xu

Ke Xu

Wenhua Zhu

Si Wang

Fujun Zhang

Manman Geng

Yan Han

Qilan Ning

Peng Xu

Liesu Meng

Shemin Lu

Affiliations

Soon will be listed here.

Abstract

Objective: The disruption of metabolic events and changes to nutrient and oxygen availability due to sustained inflammation in RA increases the demand of bioenergetic and biosynthetic processes within the damaged tissue. The current study aimed to understand the molecular mechanisms of SLC7A5 (amino acid transporter) in synoviocytes of RA patients.

Methods: Synovial tissues were obtained from OA and RA patients. Fibroblast-like synoviocytes (FLS) were isolated, and SLC7A5 expression was examined by using RT-qPCR, immunofluorescence, and Western blotting. RNAi and antibody blocking treatments were used to knockdown SLC7A5 expression or to block its transporter activities. mTOR activity assay and MMP expression levels were monitored in RA FLS under amino acid deprivation or nutrient-rich conditions.

Results: RA FLS displayed significantly upregulated expression of SLC7A5 compared to OA FLS. Cytokine IL-1β was found to play a crucial role in upregulating SLC7A5 expression via the NF-κB pathway. Intervening SLC7A5 expression with RNAi or blocking its function by monoclonal antibody ameliorated MMP3 and MMP13 protein expression. Conversely, upregulation of SLC7A5 or tryptophan supplementation enhanced mTOR-P70S6K signals which promoted the protein translation of MMP3 and MMP13 in RA FLS.

Conclusion: Activated NF-κB pathway upregulates SLC7A5, which enhances the mTOR-P70S6K activity and MMP3 and MMP13 expression in RA FLS.

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References

Laplante M, Sabatini D . mTOR signaling in growth control and disease. Cell. 2012; 149(2):274-93. PMC: 3331679. DOI: 10.1016/j.cell.2012.03.017. View

Poncet N, Mitchell F, Ibrahim A, McGuire V, English G, Arthur J . The catalytic subunit of the system L1 amino acid transporter (slc7a5) facilitates nutrient signalling in mouse skeletal muscle. PLoS One. 2014; 9(2):e89547. PMC: 3935884. DOI: 10.1371/journal.pone.0089547. View

Brenchley P . Angiogenesis in inflammatory joint disease: a target for therapeutic intervention. Clin Exp Immunol. 2000; 121(3):426-9. PMC: 1905731. DOI: 10.1046/j.1365-2249.2000.01299.x. View

Sinclair L, Rolf J, Emslie E, Shi Y, Taylor P, Cantrell D . Control of amino-acid transport by antigen receptors coordinates the metabolic reprogramming essential for T cell differentiation. Nat Immunol. 2013; 14(5):500-8. PMC: 3672957. DOI: 10.1038/ni.2556. View

Ito S, Kimura K, Haneda M, Ishida Y, Sawada M, Isobe K . Induction of matrix metalloproteinases (MMP3, MMP12 and MMP13) expression in the microglia by amyloid-beta stimulation via the PI3K/Akt pathway. Exp Gerontol. 2007; 42(6):532-7. DOI: 10.1016/j.exger.2006.11.012. View

Hara K, Yonezawa K, Weng Q, Kozlowski M, Belham C, Avruch J . Amino acid sufficiency and mTOR regulate p70 S6 kinase and eIF-4E BP1 through a common effector mechanism. J Biol Chem. 1998; 273(23):14484-94. DOI: 10.1074/jbc.273.23.14484. View

Kotake S, Udagawa N, Takahashi N, Matsuzaki K, Itoh K, Ishiyama S . IL-17 in synovial fluids from patients with rheumatoid arthritis is a potent stimulator of osteoclastogenesis. J Clin Invest. 1999; 103(9):1345-52. PMC: 408356. DOI: 10.1172/JCI5703. View

Yu Z, Lin W, Rui Z, Jihong P . Fibroblast-like synoviocyte migration is enhanced by IL-17-mediated overexpression of L-type amino acid transporter 1 (LAT1) via the mTOR/4E-BP1 pathway. Amino Acids. 2017; 50(2):331-340. DOI: 10.1007/s00726-017-2520-4. View

Su Z, Yang R, Zhang W, Xu L, Zhong Y, Yin Y . The synergistic interaction between the calcineurin B subunit and IFN-γ enhances macrophage antitumor activity. Cell Death Dis. 2015; 6:e1740. PMC: 4669720. DOI: 10.1038/cddis.2015.92. View

10.

Hua S, Dias T . Hypoxia-Inducible Factor (HIF) as a Target for Novel Therapies in Rheumatoid Arthritis. Front Pharmacol. 2016; 7:184. PMC: 4921475. DOI: 10.3389/fphar.2016.00184. View

11.

Galluccio M, Pingitore P, Scalise M, Indiveri C . Cloning, large scale over-expression in E. coli and purification of the components of the human LAT 1 (SLC7A5) amino acid transporter. Protein J. 2013; 32(6):442-8. DOI: 10.1007/s10930-013-9503-4. View

12.

Sato Y, Heimeier R, Li C, Deng C, Shi Y . Extracellular domain of CD98hc is required for early murine development. Cell Biosci. 2011; 1(1):7. PMC: 3125211. DOI: 10.1186/2045-3701-1-7. View

13.

Mastroberardino L, Spindler B, Pfeiffer R, Skelly P, Loffing J, Shoemaker C . Amino-acid transport by heterodimers of 4F2hc/CD98 and members of a permease family. Nature. 1998; 395(6699):288-91. DOI: 10.1038/26246. View

14.

Li X, Makarov S . An essential role of NF-kappaB in the "tumor-like" phenotype of arthritic synoviocytes. Proc Natl Acad Sci U S A. 2006; 103(46):17432-7. PMC: 1859946. DOI: 10.1073/pnas.0607939103. View

15.

Friesema E, Docter R, Moerings E, Verrey F, Krenning E, Hennemann G . Thyroid hormone transport by the heterodimeric human system L amino acid transporter. Endocrinology. 2001; 142(10):4339-48. DOI: 10.1210/endo.142.10.8418. View

16.

Elorza A, Soro-Arnaiz I, Melendez-Rodriguez F, Rodriguez-Vaello V, Marsboom G, de Carcer G . HIF2α acts as an mTORC1 activator through the amino acid carrier SLC7A5. Mol Cell. 2012; 48(5):681-91. DOI: 10.1016/j.molcel.2012.09.017. View

17.

Priori R, Scrivo R, Brandt J, Valerio M, Casadei L, Valesini G . Metabolomics in rheumatic diseases: the potential of an emerging methodology for improved patient diagnosis, prognosis, and treatment efficacy. Autoimmun Rev. 2013; 12(10):1022-30. DOI: 10.1016/j.autrev.2013.04.002. View

18.

Bartok B, Firestein G . Fibroblast-like synoviocytes: key effector cells in rheumatoid arthritis. Immunol Rev. 2010; 233(1):233-55. PMC: 2913689. DOI: 10.1111/j.0105-2896.2009.00859.x. View

19.

Fassbender H . The potential aggressiveness of synovial tissue in rheumatoid arthritis. J Pathol. 1983; 139(3):399-406. DOI: 10.1002/path.1711390314. View

20.

Xiong Y, Kotian S, Zeiger M, Zhang L, Kebebew E . miR-126-3p Inhibits Thyroid Cancer Cell Growth and Metastasis, and Is Associated with Aggressive Thyroid Cancer. PLoS One. 2015; 10(8):e0130496. PMC: 4526518. DOI: 10.1371/journal.pone.0130496. View