Dataset Information

Engulfment gene ELMO1 in neutrophils as a promoter of inflammatory arthritis

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE122412 | GEO | 2019/03/19

REPOSITORIES: GEO

ACCESS DATA

Similar Datasets

Project description:Baker2013 - Cytokine Mediated Inflammation in Rheumatoid Arthritis This model by Baker M. 2013, describes the interaction between pro and anti-inflammatory cytokine signalling in rheumatoid arthritis. Using two ordinary differential equations, the first model [BIOMD0000000550] analyses bifurcation and describes different pathological states by altering inflammatory regulation parameters. The second model [BIOMD0000000549] includes the effect that ageing has on pro-inflammatory signalling, allowing for time-dependant properties and disease progression to be observed. The author also describes potential dosing for reversal of the disease state. This model is described in the article: Mathematical modelling of cytokine-mediated inflammation in rheumatoid arthritis. Baker M, Denman-Johnson S, Brook BS, Gaywood I, Owen MR. Math Med Biol 2013 Dec; 30(4): 311-337 Abstract: Rheumatoid arthritis (RA) is a chronic inflammatory disease preferentially affecting the joints and leading, if untreated, to progressive joint damage and disability. Cytokines, a group of small inducible proteins, which act as intercellular messengers, are key regulators of the inflammation that characterizes RA. They can be classified into pro-inflammatory and anti-inflammatory groups. Numerous cytokines have been implicated in the regulation of RA with complex up and down regulatory interactions. This paper considers a two-variable model for the interactions between pro-inflammatory and anti-inflammatory cytokines, and demonstrates that mathematical modelling may be used to investigate the involvement of cytokines in the disease process. The model displays a range of possible behaviours, such as bistability and oscillations, which are strongly reminiscent of the behaviour of RA e.g. genetic susceptibility and remitting-relapsing disease. We also show that the dose regimen as well as the dose level are important factors in RA treatments. This model is hosted on BioModels Database and identified by: BIOMD0000000550. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

Project description:Baker2013 - Cytokine Mediated Inflammation in Rheumatoid Arthritis - Age Dependant This model by Baker M. 2013, describes the interaction between pro and anti-inflammatory cytokine signalling in rheumatoid arthritis. Using two ordinary differential equations, the first model [BIOMD0000000550] analyses bifurcation and describes different pathological states by altering inflammatory regulation parameters. The second model [BIOMD0000000549] includes the effect that ageing has on pro-inflammatory signalling, allowing for time-dependant properties and disease progression to be observed. The author also describes potential dosing for reversal of the disease state. This model is described in the article: Mathematical modelling of cytokine-mediated inflammation in rheumatoid arthritis. Baker M, Denman-Johnson S, Brook BS, Gaywood I, Owen MR. Math Med Biol 2013 Dec; 30(4): 311-337 Abstract: Rheumatoid arthritis (RA) is a chronic inflammatory disease preferentially affecting the joints and leading, if untreated, to progressive joint damage and disability. Cytokines, a group of small inducible proteins, which act as intercellular messengers, are key regulators of the inflammation that characterizes RA. They can be classified into pro-inflammatory and anti-inflammatory groups. Numerous cytokines have been implicated in the regulation of RA with complex up and down regulatory interactions. This paper considers a two-variable model for the interactions between pro-inflammatory and anti-inflammatory cytokines, and demonstrates that mathematical modelling may be used to investigate the involvement of cytokines in the disease process. The model displays a range of possible behaviours, such as bistability and oscillations, which are strongly reminiscent of the behaviour of RA e.g. genetic susceptibility and remitting-relapsing disease. We also show that the dose regimen as well as the dose level are important factors in RA treatments. This model is hosted on BioModels Database and identified by: BIOMD0000000549. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

Dataset Information

Engulfment gene ELMO1 in neutrophils as a promoter of inflammatory arthritis

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure