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Association between premature vascular smooth muscle cells senescence and vascular inflammation in Takayasu’s arteritis
  1. Chenglong Fang1,
  2. Lihong Du1,
  3. Shang Gao2,3,
  4. Yuexin Chen4,
  5. Zuoguan Chen2,
  6. Zhiyuan Wu2,
  7. Lili Li5,
  8. Jing Li1,
  9. Xiaofeng Zeng1,
  10. Mengtao Li1,
  11. Yongjun Li2,
  12. Xinping Tian1
  1. 1Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), Ministry of Science & Technology, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing, China
  2. 2Department of Vascular Surgery, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China
  3. 3Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
  4. 4Department of Vascular Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
  5. 5The State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, Beijing, China
  1. Correspondence to Professor Xinping Tian, Department of Rheumatology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, National Clinical Research Center for Immunologic Diseases, Ministry of Science & Technology, Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing, China; tianxp6{at}126.com

Abstract

Objectives Arterial wall inflammation and remodelling are the characteristic features of Takayasu’s arteritis (TAK). It has been proposed that vascular smooth muscle cells (VSMCs) are the main targeted cells of inflammatory damage and participate in arterial remodelling in TAK. Whether VSMCs are actively involved in arterial wall inflammation has not been elucidated. Studies have shown that cellular senescence in tissue is closely related to local inflammation persistence. We aimed to investigate whether VSMCs senescence contributes to vascular inflammation and the prosenescent factors in TAK.

Methods VSMCs senescence and senescence-associated secretory phenotype were detected by histological examination, bulk RNA-Seq and single-cell RNA-seq conducted on vascular surgery samples of TAK patients. The key prosenescent factors and the downstream signalling pathway were investigated in a series of in vitro and ex vivo experiments.

Results Histological findings, primary cell culture and transcriptomic analyses demonstrated that VSMCs of TAK patients had the features of premature senescence and contributed substantially to vascular inflammation by upregulating the expression of senescence-associated inflammatory cytokines. IL-6 was found to be the critical cytokine that drove VSMCs senescence and senescence-associated mitochondrial dysfunction in TAK. Mechanistically, IL-6-induced non-canonical mitochondrial localisation of phosphorylated STAT3 (Tyr705) prevented mitofusin 2 (MFN2) from proteasomal degradation, and subsequently promoted senescence-associated mitochondrial dysfunction and VSMCs senescence. Mitochondrial STAT3 or MFN2 inhibition ameliorated VSMCs senescence in ex vivo cultured arteries of TAK patients.

Conclusions VSMCs present features of cellular senescence and are actively involved in vascular inflammation in TAK. Vascular IL-6-mitochondrial STAT3-MFN2 signalling is an important driver of VSMCs senescence.

  • Autoimmune Diseases
  • Systemic vasculitis
  • Vasculitis

Data availability statement

Data are available on reasonable request. The data presented in the study are deposited in the Genome Sequence Archive for Human, accession number HRA001329 (https://bigd.big.ac.cn/gsa-human/browse/HRA001329); OMIX platform (https://ngdc.cncb.ac.cn/omix: accession no.OMIX006324); Gene Expression Omnibus platform with the accession number GSE255031 and figshare platform (https://doi.org/10.6084/m9.figshare.25664889.v1, https://doi.org/10.6084/m9.figshare.25665099.v1)

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Data availability statement

Data are available on reasonable request. The data presented in the study are deposited in the Genome Sequence Archive for Human, accession number HRA001329 (https://bigd.big.ac.cn/gsa-human/browse/HRA001329); OMIX platform (https://ngdc.cncb.ac.cn/omix: accession no.OMIX006324); Gene Expression Omnibus platform with the accession number GSE255031 and figshare platform (https://doi.org/10.6084/m9.figshare.25664889.v1, https://doi.org/10.6084/m9.figshare.25665099.v1)

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Footnotes

  • CF, LD and SG are joint first authors.

  • Handling editor Josef S Smolen

  • ML, YL and XT contributed equally.

  • Contributors CF, LD and SG are joint first authors. YL, ML and XT obtained funding. XT and YL designed the study. CF, LD, SG, ZC, LL, JL and YC conducted the experiments and collected the data. CF, LD and LL analysed the experimental data. LD interpreted the results of bulk and single-cell RNA-Seq. CF, LD, SG, ZW and YC drafted the manuscript. CF, LD, ZC, ZW and XT contributed to the interpretation of the results. All authors have read and approved the final manuscript. ML, YL and XT are co-corresponding authors and contributed equally to this study. XT is responsible for the overall content as the guarantor.

  • Funding This study was supported by the CAMS Innovation Fund for Medical Sciences (CIFMS) (2021-I2M-1-005), the National Key Research and Development Program of China (2019YFC0840603), National High Level Hospital Clinical Research Funding (2022-PUMCH-B-013, 2022-PUMCH-D-009, BJ-2021-196) and National Key Research and Development Project of China (2020YFC2008003).

  • 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.