Unknown,Transcriptomics,Genomics,Proteomics

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Synovial gene changes as a response to CpG-Stat3-siRNA treatment of mice with Antigen-Induced Arthritis (AIA).

ABSTRACT: Joint pathology in rheumatoid arthritis is broadly classified as fibroblast-rich, myeloid-rich, or lymphoid-rich synovitis. How these pathotypes evolve is unknown. Based on the clinical efficacy of biological medicines and targeted inhibitors, we hypothesise that cytokines instruct this process, affecting the rate of onset, severity, and course of disease. These include cytokine signals that define the organisation and maintenance of lymphocyte sentinels in lymphoid-rich synovitis, and others that guide a pauci-immune pathology involving activated stromal cells in fibroblast-rich synovitis. With a long-standing interest in the IL-6 cytokine family, we have identified distinct roles for Jak-STAT signalling in shaping synovitis heterogeneity. Establishing new mouse models that mimic fibroblast-rich, myeloid-rich, and lymphoid-rich synovitis in humans, we propose that wild-type (WT), Il6ra-/-, and Il27ra-/- mice with AIA share hallmarks of these pathotypes. The reported RNA-seq profiles changes in synovial gene regulation following treatment of WT and Il27ra-/- mice with CpG-Stat3-siRNA. Data was captured at day-3 and day-10 of AIA reflecting early and established disease.

INSTRUMENT(S): Illumina HiSeq 4000

ORGANISM(S): Mus musculus

SUBMITTER: Reuben Noy Scott

PROVIDER: E-MTAB-16740 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Background: Rheumatoid arthritis (RA) is a complex heterogenous autoimmune disease and achieving long term disease remission is an elusive goal for patients, thus implying improvement in drug targeting is necessary. Kinases are intracellular signalling mediators and key to sustaining the inflammatory process in RA. Therefore, oral inhibitors of specific kinases, such as Cyclin Dependent Kinases (CDKs) and Janus Kinase (JAKs), are under development or have been approved. However, the cell signalling mechanisms in treatment naïve RA patients is yet to be explored, which may facilitate targeted therapy stratification. Methods: We undertook phosphoproteome and total proteome analysis of 8 pre-treatment synovial biopsies of RA patients using label-free mass spectrometry. Results: The analysis revealed a clear separation of the phosphoproteome and proteome profile between the lymphoid and myeloid RA pathotypes. Differential expression analysis and function enrichment showed that the degree of inflammatory state and specific signalling activities are associated with different RA pathotypes. The lymphoid pathotype was enriched with immunological pathways and associated with Mammalian Target Of Rapamycin (MTOR) signalling, whereas the myeloid pathotype was associated with Mitogen-Activated Protein Kinase (MAPK) and CDK mediated signalling. This analysis also highlighted kinases not previously linked to RA, such as Serine/Threonine Protein Kinase N1 (PKN1) in the lymphoid pathotype and Protein Kinase, DNA-Activated, Catalytic Subunit (PRKDC) in the myeloid pathotypes. Certain phosphosites were also highly correlated with clinical features, such as Disabled Homolog 2 (DAB2)-Ser723 with Disease Activity Score (DAS)-28, and so these may be potential biomarkers of disease progression and response. Conclusions: These data provide evidence that specific phosphoproteome and proteome signatures are associated with different RA pathotypes and may have clinical utility for stratifying patients as part of a personalised medicine approach.

Project description:Rheumatoid synoviocytes, which consist of fibroblast-like synoviocytes (FLS) and synovial macrophages (SM), are crucial for the progression of rheumatoid arthritis (RA). Particularly, FLS of RA patients (RA-FLS) exhibit invasive characteristics reminiscent of cancer cells, destroying cartilage and bone, although it remains unresolved how RA-FLS exhibit invasive phenotype. RA-FLS and SM originate differently from mesenchymal and myeloid cells, respectively, but share many pathologic functions. However, the molecular signatures and biological networks representing the distinct and shared features of the two cell types are unknown. Presently, we performed global transcriptome profiling of FLS and SM obtained from RA and osteoarthritis patients. By comparing the transcriptomes, we identified distinct molecular signatures and cellular processes defining invasiveness of RA-FLS and pro-inflammatory properties of RA synovial macrophages (RA-SM), respectively. Interestingly, under interleukin1β-stimulated condition, RA-FLS newly acquired pro-inflammatory signature mimicking RA-SM without losing invasive properties. We next reconstructed a network model that delineates the shared, RA-FLS-dominant (invasive), and RA-SM-dominant (inflammatory) processes. From the network model, we selected 13 genes, including POSTN and TWIST1, as novel regulator candidates responsible for FLS invasiveness. Of note, POSTN and TWIST1 expressions were elevated in independent RA-FLS and were further instigated by interleukin1β. In vitro functional assays demonstrated the requirement of POSTN and TWIST1 for migration and invasion of RA-FLS stimulated with interleukin1β. Taken together, our systems approach to rheumatoid synovitis provides a basis for identifying novel regulators responsible for pathological features of RA-FLS and RA-SM, demonstrating how a certain type of cells acquires functional redundancy under chronic inflammatory conditions. To identify molecular signatures of FLS and MLS in RA joints, we isolated FLS from synovial tissues of RA and osteoarthritis (OA) patients, obtained synovial macrophages from synovial fluid of RA patients, and differentiated control macrophages from peripheral blood of healthy subjects. Also, we stimulated FLS with IL1β, and then analyzed gene expression profiles of both IL1β-stimulated RA-FLS and OA-FLS

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Synovial gene changes as a response to CpG-Stat3-siRNA treatment of mice with Antigen-Induced Arthritis (AIA).

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