Neutrophil extracellular traps trigger inflammatory bone destruction in periodontitis
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE228021 | GEO | 2023/05/23
REPOSITORIES: GEO
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Project description:Neutrophil Extracellular Traps (NETs) are chromatin-derived extracellular structures that are expelled from neutrophils in response to infectious or inflammatory stimuli. NET DNA structures are decorated with proteins including histones, myeloperoxidase and neutrophil elastase. NETs are implicated in the development of auto-immunity in diseases including rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) through the externalisation of intracellular neoepitopes e.g. dsDNA and nuclear proteins in SLE and citrullinated peptides in RA. The aim of this work was to use quantitative proteomics to identify and measure NET proteins produced by neutrophils from healthy individuals, and from patients with RA and SLE.
2019-02-18 | PXD011796 | Pride
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
Project description:Introduction: Autoreactivity to histones is a pervasive feature of several human autoimmune disorders including systemic lupus erythematosus (SLE). Specific post-translational modifications (PTMs) of histones within neutrophil extracellular traps (NETs) may potentially drive the process by which tolerance to these chromatin-associated proteins is broken. We hypothesized that NETs and their unique histone PTMs might be capable of inducing autoantibodies that target histones. Methods: We developed a novel and efficient method for the in vitro production, visualization, and broad profiling of histone-PTMs of human and murine NETs. We also immunized Balb/c mice with murine NETs and profiled their sera on autoantigen and histone peptide microarrays for evidence of autoantibody production to their immunogen. Results: We confirmed specificity toward acetyl-modified histone H2B as well as to other histone PTMs in sera from patients with SLE known to have autoreactivity against histones. We observed enrichment for distinctive histone marks of transcriptionally silent DNA during NETosis triggered by diverse stimuli. However, NETs derived from human and murine sources did not harbor many of the PTMs toward which autoreactivity was observed in patients with SLE or in MRL/lpr mice. Further, while murine NETs were weak autoantigens in vivo, there was only partial overlap in the IgG and IgM autoantibody profiles induced by vaccination of mice with NETs and those seen in patients with SLE. Conclusions: Isolated in vivo exposure to NETs is insufficient to break tolerance and may involve additional factors that have yet to be identified. Serum samples from 20 systemic lupus erythematosis patients were run on the Human Epigenome Microarray Platform V1.0 (HEMP; a single-color platform), in order to profile their autoantibodies against a library of post-translationally modified histone peptides. These 20 samples were randomly selected from a larger cohort previously profiled (data not shown) on the Utz Lab Whole Protein Autoantigen Array V2.0 (a single-color platform), where 14 were histone-reactive and 6 were histone-nonreactive. Control sera from 9 healthy adults and a positive control comprising a mixture of autoimmune sera with defined reactivities, were also run on HEMP V1.0. Together, these samples comprise the data appearing in Figures 1 and S1 (IgG and IgM isotype reactivity profiles, respectively), identifying IgG reactivity to 9 peptides that significantly distinguish histone-reactive from -nonreactive sera among 96 peptides profiled. For data appearing in Figure 5, serum samples from a total of 6 Balb/c mice, consisting of two treatment groups, NETs (Neutrophil Extracellular Traps) and NETs + CRAMP (cathelicidin-related antimicrobial peptide) were collected monthly over a 3-month period, along with a zero time point. These samples were compared with a positive control consisting of serum collected from a MLR/lpr mice exhibiting lupus-like symptoms, and a negative control with no serum. The 0, 1 and 2 month time points were profiled on the Utz Lab Whole Protein Autoantigen Array V2.0 and are shown in Figure 5A-B, while the 1 and 3 month time points were profiled on HEMP V1.0 arrays and shown in Figure 5E. All samples were run once with no replicates.
2012-01-26 | E-GEOD-32542 | biostudies-arrayexpress
Project description:Introduction: Autoreactivity to histones is a pervasive feature of several human autoimmune disorders including systemic lupus erythematosus (SLE). Specific post-translational modifications (PTMs) of histones within neutrophil extracellular traps (NETs) may potentially drive the process by which tolerance to these chromatin-associated proteins is broken. We hypothesized that NETs and their unique histone PTMs might be capable of inducing autoantibodies that target histones. Methods: We developed a novel and efficient method for the in vitro production, visualization, and broad profiling of histone-PTMs of human and murine NETs. We also immunized Balb/c mice with murine NETs and profiled their sera on autoantigen and histone peptide microarrays for evidence of autoantibody production to their immunogen. Results: We confirmed specificity toward acetyl-modified histone H2B as well as to other histone PTMs in sera from patients with SLE known to have autoreactivity against histones. We observed enrichment for distinctive histone marks of transcriptionally silent DNA during NETosis triggered by diverse stimuli. However, NETs derived from human and murine sources did not harbor many of the PTMs toward which autoreactivity was observed in patients with SLE or in MRL/lpr mice. Further, while murine NETs were weak autoantigens in vivo, there was only partial overlap in the IgG and IgM autoantibody profiles induced by vaccination of mice with NETs and those seen in patients with SLE. Conclusions: Isolated in vivo exposure to NETs is insufficient to break tolerance and may involve additional factors that have yet to be identified. Serum samples from 20 systemic lupus erythematosis patients were run on the Human Epigenome Microarray Platform V1.0 (HEMP; a single-color platform), in order to profile their autoantibodies against a library of post-translationally modified histone peptides. These 20 samples were randomly selected from a larger cohort previously profiled (data not shown) on the Utz Lab Whole Protein Autoantigen Array V2.0 (a single-color platform), where 14 were histone-reactive and 6 were histone-nonreactive. Control sera from 9 healthy adults and a positive control comprising a mixture of autoimmune sera with defined reactivities, were also run on HEMP V1.0. Together, these samples comprise the data appearing in Figures 1 and S1 (IgG and IgM isotype reactivity profiles, respectively), identifying IgG reactivity to 9 peptides that significantly distinguish histone-reactive from -nonreactive sera among 96 peptides profiled. For data appearing in Figure 5, serum samples from a total of 6 Balb/c mice, consisting of two treatment groups, NETs (Neutrophil Extracellular Traps) and NETs + CRAMP (cathelicidin-related antimicrobial peptide) were collected monthly over a 3-month period, along with a zero time point. These samples were compared with a positive control consisting of serum collected from a MLR/lpr mice exhibiting lupus-like symptoms, and a negative control with no serum. The 0, 1 and 2 month time points were profiled on the Utz Lab Whole Protein Autoantigen Array V2.0 and are shown in Figure 5A-B, while the 1 and 3 month time points were profiled on HEMP V1.0 arrays and shown in Figure 5E. All samples were run once with no replicates.
2012-01-26 | E-GEOD-32543 | biostudies-arrayexpress
Project description:Introduction: Autoreactivity to histones is a pervasive feature of several human autoimmune disorders including systemic lupus erythematosus (SLE). Specific post-translational modifications (PTMs) of histones within neutrophil extracellular traps (NETs) may potentially drive the process by which tolerance to these chromatin-associated proteins is broken. We hypothesized that NETs and their unique histone PTMs might be capable of inducing autoantibodies that target histones. Methods: We developed a novel and efficient method for the in vitro production, visualization, and broad profiling of histone-PTMs of human and murine NETs. We also immunized Balb/c mice with murine NETs and profiled their sera on autoantigen and histone peptide microarrays for evidence of autoantibody production to their immunogen. Results: We confirmed specificity toward acetyl-modified histone H2B as well as to other histone PTMs in sera from patients with SLE known to have autoreactivity against histones. We observed enrichment for distinctive histone marks of transcriptionally silent DNA during NETosis triggered by diverse stimuli. However, NETs derived from human and murine sources did not harbor many of the PTMs toward which autoreactivity was observed in patients with SLE or in MRL/lpr mice. Further, while murine NETs were weak autoantigens in vivo, there was only partial overlap in the IgG and IgM autoantibody profiles induced by vaccination of mice with NETs and those seen in patients with SLE. Conclusions: Isolated in vivo exposure to NETs is insufficient to break tolerance and may involve additional factors that have yet to be identified.
2012-01-26 | GSE32543 | GEO
Project description:Introduction: Autoreactivity to histones is a pervasive feature of several human autoimmune disorders including systemic lupus erythematosus (SLE). Specific post-translational modifications (PTMs) of histones within neutrophil extracellular traps (NETs) may potentially drive the process by which tolerance to these chromatin-associated proteins is broken. We hypothesized that NETs and their unique histone PTMs might be capable of inducing autoantibodies that target histones. Methods: We developed a novel and efficient method for the in vitro production, visualization, and broad profiling of histone-PTMs of human and murine NETs. We also immunized Balb/c mice with murine NETs and profiled their sera on autoantigen and histone peptide microarrays for evidence of autoantibody production to their immunogen. Results: We confirmed specificity toward acetyl-modified histone H2B as well as to other histone PTMs in sera from patients with SLE known to have autoreactivity against histones. We observed enrichment for distinctive histone marks of transcriptionally silent DNA during NETosis triggered by diverse stimuli. However, NETs derived from human and murine sources did not harbor many of the PTMs toward which autoreactivity was observed in patients with SLE or in MRL/lpr mice. Further, while murine NETs were weak autoantigens in vivo, there was only partial overlap in the IgG and IgM autoantibody profiles induced by vaccination of mice with NETs and those seen in patients with SLE. Conclusions: Isolated in vivo exposure to NETs is insufficient to break tolerance and may involve additional factors that have yet to be identified.
2012-01-26 | GSE32542 | GEO
Project description:Neutrophil extracellular traps (NETs) contribute to inflammatory pathogenesis, especially in infectious and cardiovascular diseases. H2 gas acts as an antioxidant and has been clinically and experimentally proven to ameliorate inflammation. Therefore, we investigated whether H2 gas could inhibit NET formation associated with excessive neutrophil activation. Phorbol-12-myristate-13-acetate (PMA)-stimulated human neutrophils exposed to H2 exhibited reduced citrullination of histones, membrane disruption by chromatin complexes, and release of NET components over controls. Mechanistically, H2 suppressed the phosphorylation of Ser-139 residue in H2AX, a marker of DNA damage, thereby reducing the expression of CXC-chemokine receptor 4 (CXCR4) in PMA-stimulated neutrophils. Along with the upregulation of CXCR4, the intracellular content of myeloperoxidase (MPO) and the production of MPO-derived hypochlorous acid (HOCl) was increased; however, these effects were markedly suppressed in H2-exposed cultures. Thus, H2 neutralized HOCl produced by the oxidative burst, inhibited DNA damage, and subsequently inhibited NET formation. We further confirmed that inhalation of H2 inhibited the formation and release of NET components in the blood and bronchoalveolar lavage of a lipopolysaccharide-induced sepsis model in mice and aged minipigs. Therefore, H2 therapy has the potential to be a new therapeutic agent for inflammatory diseases involving NETs associated with excessive neutrophil activation.
2022-02-23 | GSE178883 | GEO
Project description:Neutrophil extracellular trap (NET) release plays a key role in many chronic disease settings, including atherosclerosis. They are critical to innate immune defence, but also contribute to disease by promoting thrombosis and inflammation. Macrophages also release extracellular traps or “METs”, but their composition and role in pathological processes are less well defined. In this study, we examined MET release from human THP-1 macrophages exposed to inflammatory and pathogenic stimuli, including tumour necrosis factor alpha (TNFalpha), hypochlorous acid (HOCl) and nigericin. In each case, there was release of DNA from the macrophages, as visualised by fluorescence microscopy with the cell impermeable DNA binding dye SYTOX green, consistent with MET formation. Proteomic analysis on METs released from macrophages exposed to TNFalpha and nigericin reveals that they are composed of linker and core histones, together with a range of cytosolic and mitochondrial proteins. These include proteins involved in DNA binding, stress responses, cytoskeletal organisation, metabolism, inflammation, anti-microbial activity and calcium binding. Quinone oxidoreductase in particular, was highly abundant in all METs but has not been reported previously in NETs. Moreover, there was an absence of proteases in METs in contrast to NETs. Some of the MET histones, contained post-translational modifications, including acetylation and methylation of Lys but not citrullination of Arg. These data provide new insight into the potential implications of MET formation in vivo and their contributions to immune defence and pathology.
2023-05-16 | PXD039824 | Pride
Project description:This study invesigates the effects of neutrophil extracellular traps (NETs) on articular cartilage degredation and resulting autoimmune responses in rheumatoid arthritis.
2020-08-10 | GSE150466 | GEO
Project description:Cerebral Cavernous Malformation (CCM) is a brain vascular disease with various neurological symptoms. In this study, we describe the inflammatory profile in CCM and show for the first time the formation of neutrophil extracellular traps (NETs) in rodents and humans with CCM. Through RNA-seq analysis of cerebellum endothelial cells from wild-type mice and mice with anendothelial cell-specific ablation of the Ccm3 gene (Ccm3iECKO), we show that endothelial cells from Ccm3iECKO mice have anincreased expression of inflammation-related genes.
2023-10-31 | GSE246373 | GEO