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Multiplexed RNA-sequencing of 1M immune cells reveals the cellular, molecular, and genetic correlates of systemic lupus erythematosus

ABSTRACT: Systemic lupus erythematosus (SLE) is an autoimmune disease defined by a broad range of symptoms that disproportionately affects women Our knowledge of which immune cells mediate the etiology and pathogenesis of the disease remains incomplete Identifying pathogenic cells using bulk gene expression analysis is confounded by the functional overlap and frequency variation of immune cell types Here, we used multiplexed single-cell RNA-seq (scRNA-seq) to profile ~1 million peripheral blood mononuclear cells from 134 SLE cases and 58 healthy controls Cases were marked by a reduction of naive CD4+ T cells, clonal restriction of effector memory CD8+ T cells, and elevated expression of interferon-stimulated genes in classical monocytes An additional 15 cases experiencing active disease flares displayed increased expansion of effector memory CD8+ T cells and the presence of macrophages not seen in managed disease Although cell-type-specific expression contributed most to inter-individual expression variability across all cells, cell composition accounted for more variability in genes differentially expressed in cases We integrated dense genotyping data to map thousands of genetic variants, including SLE-associations, whose effects on expression are modified by cell type or interferon activation Population-scale scRNA-seq analysis reveals changes in cell composition and state associated with SLE, and when integrated with genetic data, ascribes function to disease-associated and disease-modified variants

ORGANISM(S): Homo sapiens

PROVIDER: GSE137029 | GEO | 2019/11/10

REPOSITORIES: GEO

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Project description:BACKGROUND: SLE is a complex autoimmune disease with deleterious effects on various organs. Accumulating evidence has shown abnormal vitamin B12 and one-carbon flux contribute to immune dysfunction. Transcobalamin II (TCN2) belongs to the vitamin B12-binding protein family responsible for the cellular uptake of vitamin B12. The role of TCN2 in SLE is still unclear.METHODS: We collected clinical information and blood from 51 patients with SLE and 28 healthy controls. RNA sequencing analysis, qPCR and western blot confirmed the alteration of TCN2 in disease monocytes. The correlation between TCN2 expression and clinical features and serological abnormalities was analyzed. TCN2 heterozygous knockout THP1 cells were used to explore the effects of TCN2 dysfunction on monocytes. CCK-8 assay and EdU staining were used to detect cell proliferation. ELISA was conducted to assess vitamin B12, glutathione and cytokines changes. UHPLC-MRM-MS/MS was used to detect changes in the intermediates of the one-carbon cycle. Flow cytometry is used to detect cell cycle, ROS, mitoROS and CD14 changes.RESULTS: Elevated TCN2 in monocytes was correlated positively with disease progression and specific tissue injuries. Using CD14+ monocytes and TCN2 genetically modified THP1 cell lines, we found that the TCN2 was induced by LPS in serum from SLE patients. TCN2 heterozygous knockout inhibited cellular vitamin B12 uptake and one-carbon metabolism, leading to cell proliferation arrest and decreased Toll-like receptor 4 (TLR4)-mediated CCL2 release. Methionine cycle metabolites, s-adenosylmethionine and homocysteine, rescued these effects, whereas folate treatment proved to be ineffective. Folate deficiency also failed to replicate the impact of TCN2 downregulation on THP1 inflammatory response.CONCLUSION: Our study elucidated the unique involvement of TCN2-driven one-carbon flux on SLE-associated monocyte behavior. Increased TCN2 may promote disease progression and tissue damage by enhancing one-carbon flux, fostering monocyte proliferation and exacerbating TLR4 mediated inflammatory responses. The inhibition of TCN2 may be a promising therapeutic approach to ameliorate SLE.

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Multiplexed RNA-sequencing of 1M immune cells reveals the cellular, molecular, and genetic correlates of systemic lupus erythematosus

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