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Transcriptomic, epigenetic and functional analyses implicate neutrophil diversity in the pathogenesis of systemic lupus erythematosus

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE139360 | GEO | 2019/11/22

REPOSITORIES: GEO

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Transcriptomic, epigenetic, and functional analyses implicate neutrophil diversity in the pathogenesis of systemic lupus erythematosus.

Project description:Neutrophil dysregulation is implicated in the pathogenesis of systemic lupus erythematosus (SLE). SLE is characterized by elevated levels of a pathogenic neutrophil subset known as low-density granulocytes (LDGs). The origin and phenotypic, functional, and pathogenic heterogeneity of LDGs remain to be systematically determined. Transcriptomics and epigenetic assessment of lupus LDGs, autologous normal-density neutrophils, and healthy control neutrophils was performed by bulk and single-cell RNA sequencing and assay for transposase-accessible chromatin sequencing. Functional readouts were compared among neutrophil subsets. SLE LDGs display significant transcriptional and epigenetic heterogeneity and comprise 2 subpopulations of intermediate-mature and immature neutrophils, with different degrees of chromatin accessibility and differences in transcription factor motif analysis. Differences in neutrophil extracellular trap (NET) formation, oxidized mitochondrial DNA release, chemotaxis, phagocytosis, degranulation, ability to harm the endothelium, and responses to type I interferon (IFN) stimulation are evident among LDG subsets. Compared with other immune cell subsets, LDGs display the highest expression of IFN-inducible genes. Distinct LDG subsets correlate with specific clinical features of lupus and with the presence and severity of coronary artery disease. Phenotypic, functional, and pathogenic neutrophil heterogeneity are prevalent in SLE and may promote immune dysregulation and prominent vascular damage characteristic of this disease.

| S-EPMC6911190 | biostudies-literature

Transcriptomic, epigenetic and functional analyses implicate neutrophil diversity in the pathogenesis of systemic lupus erythematosus [ATAC-seq]

Project description:Two subpopulations of low density granulocytes (LDGs) were defined in terms of different gene expression patterns, transcriptional and epigenetic features as well as functions. This study provides insights into the mechanism of immune dysregulation and the vascular damage characteristic of lupus.

2019-11-22 | GSE139359 | GEO

Transcriptomic, epigenetic and functional analyses implicate neutrophil diversity in the pathogenesis of systemic lupus erythematosus [RNA-seq]

2019-11-22 | GSE139358 | GEO

Transcriptomic, epigenetic and functional analyses implicate neutrophil diversity in the pathogenesis of systemic lupus erythematosus [scRNA-seq]

Project description:Two subpopulations of low density granulocytes (LGDs) were defined in terms of different gene expression patterns, transcriptional and epigenetic features as well as functions. This study provides insights into the mechanism of immune dysregulation and the vascular damage characteristic of lupus.

2019-12-13 | GSE142016 | GEO

Transcriptomic, epigenetic and functional analyses implicate neutrophil diversity in the pathogenesis of systemic lupus erythematosus

Project description:Transcriptomic, epigenetic and functional analyses implicate neutrophil diversity in the pathogenesis of systemic lupus erythematosus

| PRJNA579370 | ENA

Transcriptomic, epigenetic and functional analyses implicate neutrophil diversity in the pathogenesis of systemic lupus erythematosus [scRNA-seq]

Project description:Transcriptomic, epigenetic and functional analyses implicate neutrophil diversity in the pathogenesis of systemic lupus erythematosus [scRNA-seq]

| PRJNA595579 | ENA

Transcriptomic, epigenetic and functional analyses implicate neutrophil diversity in the pathogenesis of systemic lupus erythematosus [ATAC-seq]

Project description:Transcriptomic, epigenetic and functional analyses implicate neutrophil diversity in the pathogenesis of systemic lupus erythematosus [ATAC-seq]

| PRJNA579373 | ENA

Transcriptomic, epigenetic and functional analyses implicate neutrophil diversity in the pathogenesis of systemic lupus erythematosus [RNA-seq]

Project description:Transcriptomic, epigenetic and functional analyses implicate neutrophil diversity in the pathogenesis of systemic lupus erythematosus [RNA-seq]

| PRJNA579374 | ENA

Proteomic, biomechanical and functional analyses define neutrophil heterogeneity in systemic lupus erythematosus.

Project description:ObjectivesLow-density granulocytes (LDGs) are a distinct subset of proinflammatory and vasculopathic neutrophils expanded in systemic lupus erythematosus (SLE). Neutrophil trafficking and immune function are intimately linked to cellular biophysical properties. This study used proteomic, biomechanical and functional analyses to further define neutrophil heterogeneity in the context of SLE.MethodsProteomic/phosphoproteomic analyses were performed in healthy control (HC) normal density neutrophils (NDNs), SLE NDNs and autologous SLE LDGs. The biophysical properties of these neutrophil subsets were analysed by real-time deformability cytometry and lattice light-sheet microscopy. A two-dimensional endothelial flow system and a three-dimensional microfluidic microvasculature mimetic (MMM) were used to decouple the contributions of cell surface mediators and biophysical properties to neutrophil trafficking, respectively.ResultsProteomic and phosphoproteomic differences were detected between HC and SLE neutrophils and between SLE NDNs and LDGs. Increased abundance of type 1 interferon-regulated proteins and differential phosphorylation of proteins associated with cytoskeletal organisation were identified in SLE LDGs relative to SLE NDNs. The cell surface of SLE LDGs was rougher than in SLE and HC NDNs, suggesting membrane perturbances. While SLE LDGs did not display increased binding to endothelial cells in the two-dimensional assay, they were increasingly retained/trapped in the narrow channels of the lung MMM.ConclusionsModulation of the neutrophil proteome and distinct changes in biophysical properties are observed alongside differences in neutrophil trafficking. SLE LDGs may be increasingly retained in microvasculature networks, which has important pathogenic implications in the context of lupus organ damage and small vessel vasculopathy.

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Genetic association analyses implicate aberrant regulation of innate and adaptive immunity genes in the pathogenesis of systemic lupus erythematosus.

Project description:Systemic lupus erythematosus (SLE) is a genetically complex autoimmune disease characterized by loss of immune tolerance to nuclear and cell surface antigens. Previous genome-wide association studies (GWAS) had modest sample sizes, reducing their scope and reliability. Our study comprised 7,219 cases and 15,991 controls of European ancestry, constituting a new GWAS, a meta-analysis with a published GWAS and a replication study. We have mapped 43 susceptibility loci, including ten new associations. Assisted by dense genome coverage, imputation provided evidence for missense variants underpinning associations in eight genes. Other likely causal genes were established by examining associated alleles for cis-acting eQTL effects in a range of ex vivo immune cells. We found an over-representation (n = 16) of transcription factors among SLE susceptibility genes. This finding supports the view that aberrantly regulated gene expression networks in multiple cell types in both the innate and adaptive immune response contribute to the risk of developing SLE.

| S-EPMC4668589 | biostudies-literature

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