Engulfment gene ELMO1 in neutrophils as a promoter of inflammatory arthritis
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PROVIDER: PRJNA505064 | ENA |
REPOSITORIES: ENA
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Project description:Rheumatoid arthritis is an inflammatory disease of the synovial joints that affects ~1% of the human population, with severe distress due to progressive joint inflammation and deformation. When addressing the links between specific components of the apoptotic cell clearance machinery and human disease, we noted a correlation between single nucleotide polymorphisms (SNPs) in ELMO1, DOCK2, and RAC1 genes and rheumatoid arthritis. ELMO1 is a cytoplasmic adapter protein that associates with DOCK2 and RAC1 to promote cytoskeletal reorganization needed for apoptotic cell uptake by phagocytes. We initially hypothesized that, since ELMO1 is linked to apoptotic cell clearance, loss of ELMO1 would lead to increased inflammation in arthritis. Contrary to the accumulation of apoptotic cells and greater disease severity that we predicted, we observed significantly reduced joint inflammation in two models of arthritis in mice lacking ELMO1. Using genetic and cell biological approaches in vivo and ex vivo, we determined that ELMO1 deficiency significantly reduces neutrophil recruitment to inflamed joints, but does not result in general inhibition of inflammatory responses. Through proteomic analyses, we find that ELMO1 protein associates with cellular receptors that contribute to neutrophil function in arthritis, and regulates C5a and LTB4 receptor-mediated activation and early neutrophil recruitment to the joints. Neutrophil-specific transcriptomics show that ELMO1 modulates neutrophil-specific gene expression that includes genes with known linkages to human arthritis. Finally, neutrophils from the peripheral blood of human donors that carry the SNP in ELMO1 associated with arthritis display increased migratory capacity, whereas ELMO1 knockdown reduces human neutrophil migration to LTB4. These data identify key ‘non-canonical’ roles for engulfment machinery components in arthritis, and ELMO1 as an important regulator of specific neutrophil receptors and signaling linked to arthritis.
2019-03-19 | GSE122412 | GEO
Project description:The study presents: - an optimized synovium dissociation protocol for single cell RNA-sequencing studies of the human synovium. The protocol enables the isolation of high yield of viable synovial cells from prospectively collected fresh synovial biopsies from patients with inflammatory arthritis with a minimal sample droupout. The protocol is derived from the method for dissociation of cryopreserved synovia published by Donlin and colleagues (Arthritis Res. Ther. 2019). - a reference single-cell atlas of fresh human synovium in inflammatory arthritis, comprising more than 100´000 unsorted synovial scRNA-seq profiles from 27 freshly dissociated synovia of patients with different types of inflammatory arthritis. The synovial cells segregate into ten lymphoid, 14 myeloid and 17 stromal synovial cell populations and subpopulations, including synovial neutrophils, representing broadly representing the cellular heterogeneity and composition of the human synovium in inflammatory arthritis.
2024-04-21 | E-MTAB-11791 | biostudies-arrayexpress
Project description:G-CSF is a hemopoietic growth factor that has a role in steady state granulopoiesis, as well as in mature neutrophil activation and function. We developed a neutralizing monoclonal antibody to the murine G-CSF receptor (G-CSFR), which antagonizes binding of murine G-CSF and inhibits G-CSFR signalling. Anti-G-CSFR rapidly halts the progression of established disease in collagen antibody-induced arthritis (CAbIA). Neutrophil accumulation in joints is inhibited, without rendering animals neutropenic, suggesting an effect on homing to inflammatory sites. Neutrophils in the blood and arthritic joints of anti-G-CSFR treated mice show alterations in cell adhesion receptors, while anti-G-CSFR suppresses local production of proinflammatory cytokines and chemokines known to drive tissue damage. Our aim in this study was to use differential gene expression analysis of joint and blood neutrophils to more thoroughly understand the effect of G-CSFR blockade on the inflammatory response following anti-G-CSFR therapy in CAbIA. C57BL/6 mice with collagen antibody-induced arthritis were injected intra-peritoneally at day 5 with 50 μg anti-G-CSFR (n = 20 mice) or control mAb (n = 10 mice). At day 7, neutrophils (CD45+ CD11bhi Ly6G+) were sorted (BD FACSAria) from pooled digests of the knee tissues, or peripheral blood, and the RNA was extracted from 3 such experiments, giving a total of 12 samples.
2016-01-19 | E-GEOD-76966 | biostudies-arrayexpress
Project description:This study investigated neutrophils in systemic onset Juvenile Idiopathic Arthritis (sJIA), one of the most common multifactorial autoinflammatory diseases, characterized by arthritis and severe systemic inflammatory manifestations like fever, rash, hepatosplenomegaly and serositis. Neutrophil counts were markedly increased at disease onset, correlated to levels of inflammatory mediators and normalized within days after initiation of therapy with recombinant IL-1 receptor antagonist (rIL-1RA). Neutrophils isolated from 3 sJIA patients with active disease, before initiation of therapy (2 disease onset, 1 systemic flare) and 3 healthy controls were compared. A clear separation between the transcriptome of sJIA patients and HCs was observed. In total, 1068 genes were significantly upregulated and 625 genes were downregulated in sJIA; GO-analyses indicated upregulation of inflammatory processes in sJIA neutrophils compared to HCs. GSEA analyses revealed a significant enrichment with the transcriptome of neutrophils in sepsis patients. Correspondingly, neutrophils from sJIA patients during active disease displayed a primed phenotype characterized by an increased respiratory burst, CD62L shedding and degranulation of secretory vesicles. This phenotype was completely reversed in sJIA patients in remission on rIL-1RA. Our data show an important role for neutrophils in the early inflammatory phase of sJIA and a strong susceptibility of neutrophil numbers and inflammatory activity to IL-1 signaling blockade.
2018-02-12 | GSE103170 | GEO
Project description:In this study, we explored transcriptional complexity in human neutrophils from juvenile idiopathis arthritis and healthy control. We obtained differentially expressed genes among 3 ADU (active disease, untreated), 3 ADT (active disease, treated) and 2 HC (healthy control) samples using Cuffdiff2 software.
2017-06-13 | GSE92293 | GEO
Project description:Synovial fluid and blood neutrophils from 7 rheumatoid arthritis patients and 5 matched healthy controls
2018-07-11 | GSE116899 | GEO
Project description:This study includes RNA-seq profiles of neutrophils from healthy donors and patients with inflammatory arthritis.
2022-02-19 | GSE193117 | GEO
Project description:G-CSF is a hemopoietic growth factor that has a role in steady state granulopoiesis, as well as in mature neutrophil activation and function. We developed a neutralizing monoclonal antibody to the murine G-CSF receptor (G-CSFR), which antagonizes binding of murine G-CSF and inhibits G-CSFR signalling. Anti-G-CSFR rapidly halts the progression of established disease in collagen antibody-induced arthritis (CAbIA). Neutrophil accumulation in joints is inhibited, without rendering animals neutropenic, suggesting an effect on homing to inflammatory sites. Neutrophils in the blood and arthritic joints of anti-G-CSFR treated mice show alterations in cell adhesion receptors, while anti-G-CSFR suppresses local production of proinflammatory cytokines and chemokines known to drive tissue damage. Our aim in this study was to use differential gene expression analysis of joint and blood neutrophils to more thoroughly understand the effect of G-CSFR blockade on the inflammatory response following anti-G-CSFR therapy in CAbIA.
2016-01-19 | GSE76966 | GEO
Project description:We report changes in gene expression that take place in human neutrophils following migration from peripheral blood to synovial joints in patients with rheumatoid arthritis
2020-11-24 | GSE154474 | GEO
Project description: Not available
| S-EPMC6402828 | biostudies-literature