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DNA methylation patterns in monocytes associate and evolve with prognosis in undifferentiated arthritis [MACs]

ABSTRACT: Ontogenic origin of monocytic cells in the synovial fluid is currently under discussion. Also, the polarization of these cells have been described to a play a role in the pathogenic joints of arthritis patients. To answer these questions, we analyzed data from blood and SF monocytes and compared them with those of in vitro-generated monocyte-derived macrophages. All conditions were compared, and differences were characterized, considering experimental condition (MO, M-CSF or GM-CSF), compartment (blood or SF) and patient prognosis (good or poor).

ORGANISM(S): Homo sapiens

PROVIDER: GSE189422 | GEO | 2022/05/25

REPOSITORIES: GEO

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Multitiered proteome analysis displays the hyperpermeability of the rheumatoid synovial compartment for plasma proteins

Project description:Rheumatoid arthritis (RA) is characterized by synovial hyperplasia and cartilage/bone destruction. RA affects the synovial joints, the synovial lining and consequently the permeability of the synovium. As the latter is of central relevance for the distribution of systemically delivered therapeutics into synovial fluid (SF), we here assessed the protein composition of paired plasma and SF of patients diagnosed with RA at three distinct levels of depth using mass spectrometric approaches: the “total” proteome, the “total” IgG1 antibody repertoire and the RA-specific ACPA IgG1 autoantibody repertoire. The SF proteome was dominated by >150 plasma proteins, and we additionally detected several cartilage- and neutrophil-derived proteins of lower abundance. Strikingly, the plasma proteins were not only qualitatively reflected in SF but also quantitatively, independent of their size and/or other biochemical features. Also the synovial “total” IgG1 and autoreactive ACPA IgG1 repertoire highly resembled the IgG1 repertoires detected in plasma within the same patient. Our comprehensive multilayer data thus reveals that the proteome, including the dominant, most abundant (auto)antibody clones, present in SF of RA patients is a direct reflection of the proteome present in blood, spiked by the local (immune) processes within the RA joint. We thus conclude that proteins directly pass from blood into SF of these joints without substantial filtration bias. These findings thereby not only exemplify the use of in-depth multilayer proteome analyses to revisit basic concepts underlying RA pathology and to monitor the local (immune) processes destructive to cartilage, but also provide evidence indicating that (protein-based) therapeutics may equally enter SF of swollen joints and that pharmacokinetic analyses of such therapeutics in blood are directly relevant to the synovial compartment.

2025-01-21 | PXD054336 | Pride

Expression data of bone marrow and blood monocytes from patients with rheumatoid arthritis (RA) and osteoarthritis (OA)

Project description:Rheumatoid arthritis (RA) accompanies infiltration and activation of monocytes in inflamed joints. In this study we investigated dominant alterations of RA monocytes in bone marrow (BM), blood and inflamed joints. CD14+ cells from BM and blood of RA and osteoarthritis (OA) patients were profiled with Affymetrix HG U133 Plus 2.0 Arrays. Detailed functional analysis was performed with reference transcriptomes of BM precursors, monocyte blood subsets, monocyte activation and mobilization. Cytometric profiling determined monocyte subsets of CD14++CD16-, CD14++CD16+ and CD14+CD16+ cells in BM, blood and synovial fluid (SF) and ELISAs quantified the release of activation markers into SF and serum. Investigation of genes differentially expressed between RA and OA monocytes by co-expression analysis with reference transcriptomes revealed gene patterns of early myeloid precursors in RA-BM and late myeloid precursors along with reduced terminal differentiation to CD14+CD16+ monocytes in RA blood. Patterns associated with TNF/LPS stimulation were weak and more pronounced in RA blood than BM. Cytometric phenotyping of cells in BM and blood disclosed differences related to monocyte subsets and confirmed the reduced frequency of terminally differentiated CD14+CD16+ monocytes in RA blood, as suggested by transcriptome data. Monocyte activation in SF was characterized by the predominance of CD14++CD16++CD163+HLA-DR+ cells and elevated concentrations of sCD14, sCD163 and S100P. Accelerated monocytopoiesis, BM egress and migration into inflamed joints characterise increased monocyte turnover in RA. Predominant activation in the joint suggests local and primary stimulants, which may promote also adaptive immune triggering through monocytes, thus indicating their importance for diagnostic and therapeutic strategies.

2017-07-05 | GSE100786 | GEO

Parenchymal border macrophages regulate CSF flow dynamics [leptomeningeal macs]

Project description:Microglial cells are the resident macrophages of the brain. Perivascular macrophages (PVM) are also myeloid resident cells that are located at the interface between blood, CSF and brain in the perivascular space. Due to their strategic location and their ability to sample CSF content, we hypothesized that PVM might play a role in CSF flow. Using different fluorescent tracers injected either into the CSF (influx) or the brain parenchyma (efflux) we assessed their spatio-temporal distribution and found that ablation (using clodronate liposomes) or dysfunction (using genetic tools) of PVM alters CSF dynamics and patterns. Using single cell RNA sequencing, we found that PBMs can be divided in two sub-populations, and that one population of PBMs could interact with vascular smooth muscle cells, which allow arterial pulsations and subsequently CSF flow. Interestingly, aging results in altered PVM phenotype, and reversing this phenotype using macrophage specific grown factors reversed some of aging-associated dysfunctions of CSF flow. In summary, our results identify a new role of PVM in CSF flow and open new avenues for therapeutical applications targeting PVM in neurodegenerative diseases such as Alzheimer’s disease.

2022-08-31 | GSE188284 | GEO

The long-non coding RNA HOTAIR shapes the inflammatory response in joints of the lower extremity

Project description:Various forms of chronic arthritis like osteoarthritis (OA) or rheumatoid arthritis (RA) are major causes of disability and represent a global burden on health care systems. Inter- and intraindividual differences in the phenotype of arthritis often prevent early diagnosis and effective treatment. Previously, we suggested that site-specific differences in the joint stroma influence the development and the outcome of arthritis and showed that the long non-coding RNA HOTAIR is expressed exclusively in synovial fibroblasts (SF) of lower joints. Here, we further analysed the function of HOTAIR in SF and in arthritis development. We show that joint-specific HOTAIR expression in SF is stronlgy imprinted in the chromatin landscape of SF by epigenetic mechanisms. Nevertheless, HOTAIR expression in knee SF was downregulated by inflammatory cytokines. Accordingly, HOTAIR was more expressed in OA tissues than in RA tissues. Downregulation of HOTAIR regulated relevant arthritis pathways by epigenetic and transcriptional mechanisms and modified the migratory function of SF, decreased SF mediated osteoclastogenesis, and increased the attraction of B cells by SF. We propose that HOTAIR downregulation in inflammation epigenetically regulates important pathways and functions in SF, and thus modulates the phenotype of arthritis in lower extremity joints.

2023-01-01 | GSE185440 | GEO

Response of synovial fibroblasts to TNFα and IL6/sIL6R

Project description:Synovial fibroblasts (SF) are the main mesenchymal cell type constitutive in human synovial tissue. SF contribute to the homeostasis of normal joints by synthesizing extracellular matrix components and secreting the specific components of synovial fluid. SF are essential players in RA pathophysiology, they are the primary source of IL6 in the RA synovium contributing to perpetuate the inflammation in the joint. We used microarrays analysis to characterize the effector pro-inflammatory response of SF to TNFα and IL6/sIL6R signaling.

2021-06-01 | GSE132830 | GEO

G-CSF receptor targeting in inflammatory arthritis

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2016-01-19 | GSE76966 | GEO

Transcriptome profiling to identify a human effector regulatory T cell core signature

Project description:We investigated the transcriptomic landscape of human Treg in an autoimmune-associated inflammatory environment, i.e. synovial fluid (SF) from inflamed joints of Juvenile Idiopathic Arthritis (JIA) to improve our understanding of human effector Treg programming.

2021-02-23 | GSE161426 | GEO

Comparison of the DNA methylation profiles of CD14+ monocytes from human peripheral blood with DCs and MACs obtained by exposure with GM-CSF/IL-4 and GM-CSF, respectively, and with mature DCs and MACs after LPS exposure

Project description:Comparison of the DNA methylation profiles of CD14+ monocytes from human peripheral blood with derived dendritic cells (DCs) and macrophages (MACs) obtained by exposure with GM-CSF/IL-4 and GM-CSF, respectively, and with mature DCs and MACs after lipopolysaccharide (LPS) exposure The methylation profiles of bisulfite-modified DNA of human CD14+ monocytes were compared with derived immature dendritic cells (iDCs) and macrophages (iMACs) following GM-CSF/IL-4 and GM-CSF incubation, and then activation/maturation with lypopolysaccharyde (LPS) using the Infinium HumanMethylation450 BeadChips (Illumina, Inc., San Diego, CA,). This platform allows the interrogation of >485,000 methylation sites per sample at single-nucleotide resolution, and comprises an average of 17 CpG sites per gene in the 99% of RefSeq genes. 96% of CpG islands are covered, with additional coverage in CpG island shores and the regions flanking them. The samples were hybridized in the array following the manufacturer’s instructions.

2015-12-11 | GSE71837 | GEO

Epigenetic profiling to identify a human effector regulatory T cell core signature [H3K27ac]

Project description:We investigated the active enhancer landscape of human Treg in an autoimmune-associated inflammatory environment, i.e. synovial fluid (SF) from inflamed joints of Juvenile Idiopathic Arthritis (JIA) to improve our understanding of human effector Treg programming.

2021-02-23 | GSE156417 | GEO

Obesity defined molecular endotypes in the synovium of patients with osteoarthritis provides a rationale for therapeutic targeting of fibroblast subsets

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2023-04-03 | GSE219027 | GEO

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