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Systemic lupus erythematosus
Pathogenic neuropsychiatric effect of stress-induced microglial interleukin 12/23 axis in systemic lupus erythematosus
  1. Nobuya Abe1,2,
  2. Masato Tarumi1,2,
  3. Yuichiro Fujieda2,
  4. Nobuhiko Takahashi1,
  5. Kohei Karino2,
  6. Mona Uchida1,
  7. Michihito Kono2,
  8. Yuki Tanaka1,3,
  9. Rie Hasebe4,5,
  10. Masaru Kato2,
  11. Olga Amengual2,
  12. Yoshiyuki Arinuma6,
  13. Kenji Oku2,6,
  14. Wakiro Sato7,
  15. Khin Khin Tha8,9,
  16. Miwako Yamasaki10,
  17. Masahiko Watanabe10,
  18. Tatsuya Atsumi2,
  19. Masaaki Murakami1,3,5
  1. 1 Division of Molecular Psychoimmunology, Institute for Genetic Medicine, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
  2. 2 Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
  3. 3 Group of Quantum Immunology, Institute for Quantum Life Science, National Institute for Quantum and Radiological Science and Technology, Inage, Japan
  4. 4 Center for Infectious Cancers, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan
  5. 5 Division of Molecular Neuroimmunology, National Institute for Physiological Sciences, National Institute of Natural Sciences, Okazaki, Japan
  6. 6 Department of Rheumatology and Infectious Diseases, School of Medicine, Kitasato University, Sagamihara, Japan
  7. 7 Department of Immunology, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Japan
  8. 8 Department of Diagnostic and Interventional Radiology, Hokkaido University Hospital, Sapporo, Japan
  9. 9 Global Center for Biomedical Science and Engineering, Faculty of Medicine, Hokkaido University, Sapporo, Japan
  10. 10 Department of Anatomy, Faculty of Medicine, Hokkaido University, Sapporo, Japan
  1. Correspondence to Professor Masaaki Murakami, Division of Molecular Psychoimmunology, Institute for Genetic Medicine, Graduate School of Medicine, Hokkaido University, Sapporo, Japan; murakami{at}igm.hokudai.ac.jp; Professor Tatsuya Atsumi, Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine, Hokkaido University, Sapporo, Japan; at3tat{at}med.hokudai.ac.jp

Abstract

Objectives The central nervous system disorder in systemic lupus erythematosus (SLE), called neuropsychiatric lupus (NPSLE), is one of the most severe phenotypes with various clinical symptoms, including mood disorder, psychosis and delirium as diffuse neuropsychological manifestations (dNPSLE). Although stress is one of the aggravating factors for neuropsychiatric symptoms, its role in the pathogenesis of dNPSLE remains to be elucidated. We aimed to investigate stress effects on the neuropsychiatric pathophysiology in SLE using lupus-prone mice and patients’ data.

Methods Sleep disturbance stress (SDS) for 2 weeks was placed on 6–8-week-old female MRL/lpr and control mice. Behavioural phenotyping, histopathological analyses and gene and protein expression analyses were performed to assess SDS-induced neuroimmunological alterations. We also evaluated cytokines of the cerebrospinal fluid and brain regional volumes in patients with dNPSLE and patients with non-dNPSLE.

Results SDS-subjected MRL/lpr mice exhibited less anxiety-like behaviour, whereas stressed control mice showed increased anxiety. Furthermore, stress strongly activated the medial prefrontal cortex (mPFC) in SDS-subjected MRL/lpr. A transcriptome analysis of the PFC revealed the upregulation of microglial activation-related genes, including Il12b. We confirmed that stress-induced microglial activation and the upregulation of interleukin (IL) 12/23p40 proteins and increased dendritic spines in the mPFC of stressed MRL/lpr mice. IL-12/23p40 neutralisation and tyrosine kinase 2 inhibition mitigated the stress-induced neuropsychiatric phenotypes of MRL/lpr mice. We also found a higher level of cerebrospinal fluid IL-12/23p40 and more atrophy in the mPFC of patients with dNPSLE than those with non-dNPSLE.

Conclusions The microglial IL-12/23 axis in the mPFC might be associated with the pathogenesis and a promising therapeutic target for dNPSLE.

  • cytokines
  • lupus erythematosus, systemic
  • psychology
  • Magnetic Resonance Imaging
  • inflammation

Data availability statement

Data are available in a public, open access repository. Data are available upon reasonable request. In detail, RNA-seq datasets that support the observations of this study have been deposited in the Gene Expression Omnibus with the series accession number GSE176429. MRI data have been stored locally following national and Japanese laws on the protection of individuals with regard to the processing of personal data. Other data are available in the main text or the supplementary materials and are available upon reasonable request to the corresponding author.

https://doi.org/10.1136/ard-2022-222566

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    Data availability statement

    Data are available in a public, open access repository. Data are available upon reasonable request. In detail, RNA-seq datasets that support the observations of this study have been deposited in the Gene Expression Omnibus with the series accession number GSE176429. MRI data have been stored locally following national and Japanese laws on the protection of individuals with regard to the processing of personal data. Other data are available in the main text or the supplementary materials and are available upon reasonable request to the corresponding author.

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    Footnotes

    • Handling editor Josef S Smolen

    • Contributors Conceptualisation: NA and MM. Methodology: NA, NT, YF, YT, RH and KKT. Investigation: NA, NT, MT, KK, MU and KKT. Visualisation: NA and YF. Resources: YA, WS, KKT and MY. Funding acquisition and project administration: KO, TA and MM. Supervision: MKono, MKato, MY, MW, TA and MM. Writing—original draft: NA, YF and KO. Writing—review and editing: OA, KKT, MW, TA and MM. Guarantors: TA and MM.

    • Funding This work was funded by the grant from Bristol Myers Squibb Foundation to TA, and grants from JSPS KAKENHI, Q-Leap (JPMXS0120330644), AMED, The Joint Usage/Research Center Institute for Genetic Medicine, Hokkaido University, the Photo-excitonix Project at Hokkaido University and the Promotion Project for Young Investigators at Hokkaido University to MM.

    • 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.