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  • NAT10 promotes synovial aggression by increasing the stability and translation of N4-acetylated PTX3 mRNA in rheumatoid arthritis

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Rheumatoid arthritis
NAT10 promotes synovial aggression by increasing the stability and translation of N4-acetylated PTX3 mRNA in rheumatoid arthritis
  1. Di Liu1,
  2. Yu Kuang1,
  3. Simin Chen1,
  4. Ruiru Li1,
  5. Fan Su2,
  6. Shuoyang Zhang1,
  7. Qian Qiu1,
  8. Shuibin Lin3,
  9. Chuyu Shen1,
  10. Yingli Liu1,
  11. Liuqin Liang1,
  12. Jingnan Wang1,
  13. Hanshi Xu1,
  14. Youjun Xiao1
  1. 1 Department of Rheumatology and Clinical Immunology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
  2. 2 Department of Geriatrics, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
  3. 3 Center for Translational Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
  1. Correspondence to Dr Youjun Xiao; xiaoyouj{at}mail2.sysu.edu.cn; Dr Jingnan Wang; wangjn333{at}mail2.sysu.edu.cn; Dr Hanshi Xu; xuhanshi{at}mail.sysu.edu.cn

Abstract

Objective Recent studies indicate that N-acetyltransferase 10 (NAT10)-mediated ac4C modification plays unique roles in tumour metastasis and immune infiltration. This study aimed to uncover the role of NAT10-mediated ac4C in fibroblast-like synoviocytes (FLSs) functions and synovial immune cell infiltration in rheumatoid arthritis (RA).

Methods FLSs were obtained from active established patients with RA. Protein expression was determined by western blotting or immunohistochemistry or multiplexed immunohistochemistry. Cell migration was measured using a Boyden chamber. ac4C-RIP-seq combined with RNA-seq was performed to identify potential targets of NAT10. RNA immunoprecipitation was used to validate the interaction between protein and mRNA. NAT10 haploinsufficiency, inhibitor remodelin or intra-articular Adv-NAT10 was used to suppress arthritis in mice with delayed-type hypersensitivity arthritis (DYHA) and collagen II-induced arthritis (CIA) and rats with CIA.

Results We found elevated levels of NAT10 and ac4C in FLSs and synovium from patients with RA. NAT10 knockdown or specific inhibitor treatment reduced the migration and invasion of RA FLSs. Increased NAT10 level in the synovium was positively correlated with synovial infiltration of multiple types of immune cells. NAT10 inhibition in vivo attenuated the severity of arthritis in mice with CIA and DTHA, and rats with CIA. Mechanistically, we explored that NAT10 regulated RA FLS functions by promoting stability and translation efficiency of N4-acetylated PTX3 mRNA. PTX3 also regulated RA FLS aggression and is associated with synovial immune cell infiltration.

Conclusion Our findings uncover the important roles of NAT10-mediated ac4C modification in promoting rheumatoid synovial aggression and inflammation, indicating that NAT10 may be a potential target for the treatment of RA, even other dysregulated FLSs-associated disorders.

  • Arthritis, Rheumatoid
  • Fibroblasts
  • Autoimmune Diseases

Data availability statement

Data are available on reasonable request.

https://doi.org/10.1136/ard-2023-225343

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    Data availability statement

    Data are available on reasonable request.

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    Footnotes

    • Handling editor Josef S Smolen

    • DL, YK and SC contributed equally.

    • Contributors DL, YK and SC performed the majority of the experiments and analysed and interpreted the data. RL, FS and QQ collected clinical samples and analysed and interpreted the data. SZ, CS and YL performed the in vivo experiments. LL, JW, HX and YX contributed to the study concept and design. DL, YX and HX drafted the manuscript. LL, JW, HX and YX contributed to study supervision. YX was responsible for the overall content as the guarantor. No honorarium, grant or other form of payment was given to anyone to produce the manuscript.

    • Funding This work was supported by grants from the National Natural Science Foundation of China (Grants No.: 82001714, 82101880, 82271818, 82071831, 81871275, 81671591, U1401222, 81501389 and 81373182), the Fundamental Research Funds for the Central Universities of China (19ykpy59 and 17ykjc07), Guangzhou Science and Technology Project (201803010042), and Guangdong Basic and Applied Basic Research Foundation (2023A1515011768, 2021A1515010535 and 2020A1515010221).

    • Competing interests None declared.

    • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.