Article Text
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.
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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.
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.
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