Engulfment gene ELMO1 in neutrophils as a promoter of inflammatory arthritis
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ABSTRACT:
PROVIDER: PRJNA505064 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR8180960_1.fastq.gz | Fastqsanger.gz | |||
| SRR8180960_2.fastq.gz | Fastqsanger.gz | |||
| SRR8180970_1.fastq.gz | Fastqsanger.gz | |||
| SRR8180970_2.fastq.gz | Fastqsanger.gz | |||
| SRR8180961_1.fastq.gz | Fastqsanger.gz |
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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:Osteoporosis and bone fractures affect millions of men and women worldwide and are often due to increased bone resorption (bone loss) mediated by osteoclasts. Here, we identify a novel role for the cytoplasmic protein ELMO1 as an important ‘signaling node’ controlling the bone resorption function of osteoclasts. Initially, we noted association of ELMO1 SNPs with bone abnormalities and altered bone density in humans. Experimentally, ELMO1 emerged as a promoter of bone loss wherein deletion of ELMO1 reversed osteoporosis / bone erosions in four in vivo mouse models: osteoprotegerin deficiency, ovariectomy, and two types of inflammatory arthritis. However, ELMO1 did not promote bone loss under homeostatic conditions. Mechanistic studies pointed to a larger ELMO1 signaling network that regulates osteoclast activity at several levels. First, transcriptomics coupled with CRISPR/Cas9 genetic deletion approaches identified new regulators of osteoclast function associated with Elmo1. Second, defining the ‘ELMO1 interactome’ in osteoclasts via proteomics revealed proteins linked to bone degradation. Third, ELMO1 affects the formation of the actin ring /sealing zone on bone-like surfaces and the distribution of osteoclast-specific proteases. Finally, a 3D structure-based inhibitory peptide targeting a highly conserved region of ELMO1 reduced bone resorption in wild type osteoclasts. Collectively, these data identify ELMO1 as a signaling hub that regulates osteoclast function and bone loss, with relevance to diseases such as osteoporosis and arthritis.
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Project description:Engulfment and Cell Motility 1 (ELMO1) facilitates activation of Ras-related C3 botulinum toxin substrate 1 (RAC1) through interaction with Dedicator of Cytokinesis (DOCK), a family of guanine nucleotide exchange factors (GEF). ELMO1 plays an important role in acute and chronic inflammation by enhancing immune cell migration, phagocytosis of pathogens and dead cells, and production of reactive oxygen species. Endothelial cells, an integral component of inflammatory responses, also express high levels of ELMO1, although the role of ELMO1 in inflammatory endothelial cells is unclear. We demonstrate that knockdown of ELMO1 in EA.hy926 human umbilical vein endothelial cells (HUVECs) leads to cell quiescence, while protects the cells from Toll-like receptor 3 (TLR3)-induced apoptosis and restores inflammatory responses.
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Project description:Osteoporosis and bone fractures affect millions of men and women worldwide and are often due to increased bone resorption (bone loss) mediated by osteoclasts. Here, we identify a novel role for the cytoplasmic protein ELMO1 as an important ‘signaling node’ controlling the bone resorption function of osteoclasts. Initially, we noted association of ELMO1 SNPs with bone abnormalities and altered bone density in humans. Experimentally, ELMO1 emerged as a promoter of bone loss wherein deletion of ELMO1 reversed osteoporosis / bone erosions in four in vivo mouse models: osteoprotegerin deficiency, ovariectomy, and two types of inflammatory arthritis. However, ELMO1 did not promote bone loss under homeostatic conditions. Mechanistic studies pointed to a larger ELMO1 signaling network that regulates osteoclast activity at several levels. First, transcriptomics coupled with CRISPR/Cas9 genetic deletion approaches identified new regulators of osteoclast function associated with Elmo1, including cathepsin G and myeloperoxidase. Second, defining the ‘ELMO1 interactome’ in osteoclasts via proteomics revealed membrane proteins and v-ATPases required for bone degradation. Third, ELMO1 affects the formation of the actin ring /sealing zone on bone-like surfaces and the distribution of osteoclast-specific proteases. Finally, a 3D structure-based inhibitory peptide targeting a highly conserved region of ELMO1 reduced bone resorption in wild type osteoclasts. Collectively, these data identify ELMO1 as a signaling hub that regulates osteoclast function and bone loss, with relevance to diseases such as osteoporosis and arthritis.
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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.
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Project description:Synovial fluid and blood neutrophils from 7 rheumatoid arthritis patients and 5 matched healthy controls
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Project description:Rheumatoid arthritis is characterized by progressive joint inflammation and affects ~1% of the human population. We noted single-nucleotide polymorphisms (SNPs) in the apoptotic cell-engulfment genes ELMO1, DOCK2, and RAC1 linked to rheumatoid arthritis. As ELMO1 promotes cytoskeletal reorganization during engulfment, we hypothesized that ELMO1 loss would worsen inflammatory arthritis. Surprisingly, Elmo1-deficient mice showed reduced joint inflammation in acute and chronic arthritis models. Genetic and cell-biology studies revealed that ELMO1 associates with receptors linked to neutrophil function in arthritis and regulates activation and early neutrophil recruitment to the joints, without general inhibition of inflammatory responses. Further, 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 chemokines linked to arthritis. These data identify 'noncanonical' roles for ELMO1 as an important cytoplasmic regulator of specific neutrophil receptors and promoter of arthritis.
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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.
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