Abstract
Although vascular dementia (VD) and systemic lupus erythematosus (SLE) may share immune-mediated pathophysiologic processes, the underlying mechanisms are unclear. This study investigated shared gene signatures in SLE versus VD, as well as their potential molecular mechanisms. Bulk RNA sequencing (RNAseq) and single-cell or single-nucleus RNAseq (sc/snRNAseq) datasets from SLE blood samples and VD brain samples were obtained from Gene Expression Omnibus. The identification of genes associated with both SLE and VD was performed using the weighted gene co-expression network analysis (WGCNA) and machine learning algorithms. For the sc/snRNAseq data, an unbiased clustering pipeline based on Seurat and CellChat was used to determine the cellular landscape profile and examine intracellular communication, respectively. The results were subsequently validated using a mice model of SLE with cognitive dysfunction (female MRL/lpr mice). WGCNA and machine learning identified C1QA, LY96, CD163, and MS4A4A as key genes for SLE and VD. sc/snRNAseq analyses revealed that CD163 and MS4A4A were upregulated in mononuclear phagocytes (MPs) from SLE and VD samples and were associated with monocyte-macrophage differentiation. Intriguingly, LGALS9-associated molecular pathway, as the only signaling pathway common between SLE and VD via CellChat analysis, exhibited significant upregulation in cortical microglia of MRL/lpr mice. Our analyses identified C1QA, LY96, CD163, and MS4A4A as potential biomarkers for SLE and VD. Moreover, the upregulation of CD163/MS4A4A and activation of LGALS9 signaling in MPs may contribute to the pathogenesis of VD with SLE. These findings offer novel insight into the mechanisms underlying VD in SLE patients.
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Data availability
The datasets generated and analyzed during the current study are available in the NCBI GEO database (https://www.ncbi.nlm.nih.gov/). And further information is available from the corresponding author upon reasonable request.
Abbreviations
- VD:
-
Vascular dementia
- AD:
-
Alzheimer’s disease
- SLE:
-
Systemic lupus erythematosus
- DEGs:
-
Differentially expressed genes
- scRNAseq:
-
Single-cell RNA sequencing
- snRNAseq:
-
Single-nucleus RNA sequencing
- WGCNA:
-
Weighted gene correlation network analysis
- GEO:
-
Gene Expression Omnibus
- PBMC:
-
Peripheral blood mononuclear cell
- FC:
-
Fold changes
- IGs:
-
Intramodular genes
- DEIGs:
-
Differentially expressed intramodular genes
- GSEA:
-
Gene set enrichment analysis
- GSVA:
-
Gene set variation analysis
- GO:
-
Gene ontology
- KEGG:
-
Kyoto Encyclopedia of Genes and Genomes
- BP:
-
Biological process
- CC:
-
Cellular component
- MF:
-
Molecular function
- PPI:
-
Protein–protein interaction
- SVM-RFE:
-
Support vector machine-recursive feature elimination
- RF:
-
Random forest
- ROC:
-
Receiver operating characteristic
- AUC:
-
Area under the curve
- RMSE:
-
Root mean square error
- MRL/lpr:
-
Bilateral common carotid artery occlusion
- MWM:
-
Morris water maze
- RT-qPCR:
-
Reverse transcription quantitative real-time polymerase chain reaction
- MPs:
-
Mononuclear phagocytes
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This work was supported by the Scientific Research Project of Guangdong Province Traditional Chinese Medicine Bureau (grant number 20222148).
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JL was responsible for the study design. JL and JC contributed to data collection from GEO database and statistical analysis. XZ performed all experiments. CH analyzed the experimental data. JC was a major contributor in writing the manuscript. JL contributed to the revision of the manuscript. All authors read and approved the final manuscript.
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Chen, J., Zhao, X., Huang, C. et al. Novel insights into molecular signatures and pathogenic cell populations shared by systemic lupus erythematosus and vascular dementia. Funct Integr Genomics 23, 337 (2023). https://doi.org/10.1007/s10142-023-01270-2
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DOI: https://doi.org/10.1007/s10142-023-01270-2