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Human lupus netting neutrophils induce endothelial damage, infiltrate tissues and expose immunostimulatory molecules

ABSTRACT: Our group has proposed that low-density granulocytes (LDGs) play an important role in lupus pathogenesis, as they can damage endothelial cells and synthesize increased levels of proinflammatory cytokines and type I interferons. LDGs have a heightened capacity to synthesize neutrophil extracellular traps (NETs). NETs from LDGs display increased levels of bactericidal and immunostimulatory proteins, such as the cathelicidin LL37 and externalize double-stranded DNA (dsDNA). Lupus netting LDGs have increased capacity to kill endothelial cells and expose IL-17. Through NETosis, lupus neutrophils stimulate plasmacytoid DCs to synthesize IFN-α. Our results further expand the potential pathogenic role of aberrant lupus neutrophils through a NET-mediated effect. We used microarrays to analyze the gene expression of neutrophils in healthy and lupus patients, and of low-density granulocytes in lupus patients.

ORGANISM(S): Homo sapiens

PROVIDER: GSE26975 | GEO | 2011/06/22

SECONDARY ACCESSION(S): PRJNA135917

REPOSITORIES: GEO

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Human lupus netting neutrophils induce endothelial damage, infiltrate tissues and expose immunostimulatory molecules

Project description:Our group has proposed that low-density granulocytes (LDGs) play an important role in lupus pathogenesis, as they can damage endothelial cells and synthesize increased levels of proinflammatory cytokines and type I interferons. LDGs have a heightened capacity to synthesize neutrophil extracellular traps (NETs). NETs from LDGs display increased levels of bactericidal and immunostimulatory proteins, such as the cathelicidin LL37 and externalize double-stranded DNA (dsDNA). Lupus netting LDGs have increased capacity to kill endothelial cells and expose IL-17. Through NETosis, lupus neutrophils stimulate plasmacytoid DCs to synthesize IFN-?. Our results further expand the potential pathogenic role of aberrant lupus neutrophils through a NET-mediated effect. We used microarrays to analyze the gene expression of neutrophils in healthy and lupus patients, and of low-density granulocytes in lupus patients. Human neutrophils and LDGs were isolated from PBMCs. RNA from healthy neutrophils, lupus neutrophils and lupus LDGs was extracted and processed for hybridization on Affymetrix microarrays.

2011-06-22 | E-GEOD-26975 | biostudies-arrayexpress

RNA externalized by neutrophil extracellular traps promotes inflammatory pathways in endothelial cells

Project description:Abstract. Objectives: Neutrophil extracellular traps (NETs) are extracellular lattices composed of nucleic material bound to neutrophil granule proteins. NETs may play pathogenic roles in development and severity of autoimmune diseases such as systemic lupus erythematosus (SLE), at least in part, through induction of type I interferon (IFN) responses via externalization of oxidized immunostimulatory DNA. A distinct subset of SLE proinflammatory neutrophils (low density granulocytes; LDGs) displays enhanced ability to form proinflammatory NETs that damage the vasculature. We assessed whether NET-bound RNA can contribute to inflammatory responses in endothelial cells and the pathways that mediate this effect. Methods: Expression of newly-synthesized RNA was quantified if healthy control and lupus NETs. The ability of endothelial cells to take up NET-bound RNA and downstream induction of type I IFN responses was quantified. RNAs present in NETs were sequenced and specific small RNAs were tested for induction of endothelial type I IFN pathways. Results: NETs extruded newly-synthesized RNA that was internalized by endothelial cells and this was enhanced when NET nucleic acids were oxidized, particularly in lupus LDG NETs. Internalization of NET-bound total RNA by endothelial cells was dependent on endosomal TLRs and the actin cytoskeleton and induced type I IFN stimulated genes (ISGs). This ISG induction was dependent on NET-associated miR-let7b, a small RNA expressed at higher levels in LDG NETs, which acted as a TLR7 agonist. Conclusion: These results highlight underappreciated roles for small RNAs externalized in NETs in the induction of proinflammatory responses in vascular cells, with implications to lupus vasculopathy.

2023-07-31 | GSE160143 | GEO

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

Epigenome profiling reveals significant DNA demethylation of interferon signature genes in lupus neutrophils

Project description:We identified genome-wide DNA methylation patterns within neutrophils and low-density granulocytes of Lupus patients and demographically matched controls

2015-01-21 | GSE65097 | GEO

Epigenome profiling reveals significant DNA demethylation of interferon signature genes in lupus neutrophils

Project description:We identified genome-wide DNA methylation patterns within neutrophils and low-density granulocytes of Lupus patients and demographically matched controls Comparison of 15 Lupus patients vs 15 age-, sex-, and ethnicity-matched controls using the Illumina HumanMethylation 450 beadchip array

2015-01-21 | E-GEOD-65097 | biostudies-arrayexpress

Neutrophils from patients with recurring Panton-Valentine Leukocidin-positive Staphylococcus aureus infections are more sensitive to PVL induced NETosis

Project description:Panton-Valentine Leukocidin (PVL) is a Staphylococcus aureus toxin that binds to and kills human neutrophils resulting in the formation of neutrophil extracellular traps. A subset of individuals colonized with PVL expressing S. aureus suffer from recurring infections. We found that neutrophils from affected individuals display increased spontaneous NET formation after isolation, and increased sensitivity to killing by PVL. Compared to healthy controls, the expression of the target receptors for PVL, CD45 and C5L2, but not CD88, was increased in these patients, and the expression correlated to the amount of PVL-induced NETs produced. NADPH-oxidase activity was not important for PVL induced NETosis as neutrophils from CGD patients produced NETs in response to PVL. Through NET proteome analysis we identified that the protein content of PVL induced NETs is different from mitogen induced NETs. The abundance of the antimicrobial proteins LL37, myeloperoxidase, azurocidin, and proteinase 3 was lower on PVL NETs and PVL-induced NETs were deficient in killing Staphylococcus aureus. Neutrophils from patients that suffer from recurring PVL-positive infections may be more sensitive to PVL-induced NETosis, impairing their ability to combat the infection.

2023-11-23 | PXD025702 | Pride

Human Neutrophils Phosphoproteome in Systemic Lupus Erythematosus

Project description:This study used proteomic, biomechanical, and functional analyses to further define neutrophil heterogeneity in the context of SLE. Mass spectrometry proteomic and phosphoproteomic analyses were performed in healthy control normal density neutrophils (NDNs), SLE NDNs and in autologous SLE LDGs. Proteomic and phosphoproteomic differences were detected when comparing control to SLE neutrophils and when comparing SLE NDNs to SLE LDGs.

2021-11-04 | PXD021096 | Pride

Characterization of neutrophil extracellular trap-associated RNA, a novel DAMP acting in concert with the antimicrobial peptide LL37 as intentional but self-limiting drivers of inflammation

Project description:Neutrophil extracellular traps (NETs) are a key antimicrobial feature of cellular innate immunity mediated by polymorphonuclear neutrophils (PMNs). NETs trap and kill microbes but have also been linked to inflammation in atherosclerosis, arthritis, or psoriasis by unknown mechanisms. We here report that NET-associated RNA (naRNA, which was RNA-sequenced from human primary neutrophil NETs here) stimulated further NET formation in naïve PMNs via a unique TLR8-NLRP3-caspase-1-gasdermin D-dependent inflammasome pathway. Keratinocytes also responded to naRNA with expression of psoriasis-related genes (e.g. IL17, IL36) via atypical NOD2-RIPK signaling. In vivo naRNA drove skin inflammation, which was drastically ameliorated by genetic ablation of RNA sensing. The naRNA-LL37 ‘composite DAMP’ was pre-stored in resting neutrophil granules, defining sterile NETs as intentionally inflammatory webs that amplify neutrophil activation. However, the activity of the naRNA-LL37 DAMP was transient and hence supposedly self-limiting under physiological conditions. Only upon dysregulated NET release like psoriasis, TLR-NLRP3-mediated naRNA sensing may represent both potential cause of disease and new intervention target.

2024-05-06 | GSE253440 | GEO

Dysregulated neutrophil responses and neutrophil extracellular trap formation and degradation in PAPA syndrome

Project description:Pyogenic arthritis, pyoderma gangrenosum and acne (PAPA) syndrome is characterized by flares of sterile arthritis with neutrophil infiltrate and the overproduction of Interleukin (IL)-1β. The purpose of this study was to elucidate the potential role of neutrophil subsets and neutrophil extracellular traps (NETs) in the pathogenesis of PAPA. The transcriptome of PAPA normal-dense neutrophils, autologous LDGs, and healthy control normal-dense neutrophils was characterized using RNASeq. The transcriptome of a PAPA skin biopsy and a healthy control skin sample was elucidated using RNASeq.

2018-10-23 | GSE117168 | GEO

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