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Myositis
Protein kinase R is highly expressed in dermatomyositis and promotes interferon-beta-induced muscle damage
  1. Guoyong Zhang1,2,
  2. Lining Zhang3,4,
  3. Dandan Zhao3,
  4. Xiaoyu Liu1,
  5. Wei Li3,
  6. Chuanzhu Yan3,5,
  7. Tingjun Dai3
  1. 1 Department of Neurology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, People's Republic of China
  2. 2 University of Health and Rehabilitation Sciences, Qingdao, Shandong, People's Republic of China
  3. 3 Department of Neurology, Research Institute of Neuromuscular and Neurodegenerative Diseases,Qilu Hospital of Shandong University, Shandong Provincial Key Laboratory of Mitochondrial Medicine and Rare Diseases, Jinan, Shandong, People's Republic of China
  4. 4 Department of Rheumatology, Qilu Hospital of Shandong University, Jinan, Shandong, People's Republic of China
  5. 5 Qingdao Municipal Key Laboratory of Mitochondria Medicine, Qingdao, Shandong, People's Republic of China
  1. Correspondence to Professor Chuanzhu Yan; czyan{at}sdu.edu.cn; Dr Tingjun Dai; tingjundai{at}sdu.edu.cn

Abstract

Objectives Dermatomyositis (DM) has been consistently linked to the type I interferon (IFN-I) pathway. However, the precise pathogenesis remains incompletely elucidated. We aimed to explore potential molecular mechanisms and identify promising therapeutic targets in DM.

Methods We employed bioinformatics analysis to investigate molecular signatures, aiming to shed light on the pathogenesis of DM. The expression of protein kinase R (PKR) in DM muscle tissues was determined by real-time quantitative PCR, western blot and immunohistochemistry (IHC) analysis. We then assessed the sensitivity and specificity of sarcoplasmic PKR expression by IHC in a consecutive DM cohort and other diseases in this retrospective study. Furthermore, IFN-β was used to stimulate myoblasts and myotubes, and the relationship between PKR and IFN-β-induced pathogenic molecules was investigated in vitro.

Results Bioinformatics analysis indicated two primary pathological processes: viral infection and the IFN-I signalling pathway. We subsequently verified that PKR was notably expressed in the cytoplasm of myofibers in DM patients. The sensitivity and specificity of sarcoplasmic PKR expression in DM were 84.6% and 97.6%, respectively. In vitro studies revealed that IFN-β upregulates the expression of PKR, along with several molecules associated with DM muscle damage. Conversely, inhibiting PKR has been shown to downregulate IFN-β-induced pathogenic molecules in both myoblasts and myotubes.

Conclusions We observed that PKR exhibits specific expression in the cytoplasm of DM muscle and inhibiting PKR ameliorates IFN-β-induced muscle damage in vitro. These findings provide insights into the diagnostic and therapeutic roles of PKR in DM.

  • Dermatomyositis
  • Autoimmune Diseases
  • Autoimmunity

Data availability statement

Data are available upon reasonable request.

https://doi.org/10.1136/ard-2024-226057

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    Data availability statement

    Data are available upon reasonable request.

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    Footnotes

    • Handling editor Josef S Smolen

    • Contributors GYZ, CZY and TJD contributed to conception and design of the study. GYZ, LNZ, DDZ, XYL and WL contributed to acquisition and analysis of data. GYZ, CZY and TJD contributed to drafting the text or preparing the figures. TJD is the guarantor.

    • Funding This study was supported by the National Key Research and Development Program of China (2021YFC2700904); the National Natural Science Foundations of China (No. 82071412, 82171395); the Taishan Scholars Program of Shandong Province, Qingdao Technology Program for Health and Welfare (20–3-4–42-nsh); and the 20-policy supported projects of collaborative innovation and achievement transformation in universities and research institutes of Jinan (2019GXRC050).

    • Competing interests None declared. Schematic diagram was created by Figdraw (www.figdraw.com).

    • Patient and public involvement Patients and/or the public were not involved in the design, conduct, 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.