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Immunology Letters Nov 2023Synovial fibroblasts are critical for maintaining homeostasis in major autoimmune diseases involving joint inflammation, including osteoarthritis and rheumatoid...
BACKGROUND
Synovial fibroblasts are critical for maintaining homeostasis in major autoimmune diseases involving joint inflammation, including osteoarthritis and rheumatoid arthritis. However, little is known about the interactions among different cell subtypes and the specific sets of signaling pathways and activities that they trigger.
METHODS
Using social network analysis, pattern recognition, and manifold learning approaches, we identified patterns of single-cell communication in OA (osteoarthritis) and RA (rheumatoid arthritis).
RESULTS
Our results suggest that OA and RA have distinct cellular communication patterns and signaling pathways. The LAMININ (Laminin) and COLLAGEN (Collagen) pathways predominate in osteoarthritis, while the EGF (Epidermal growth factor), NT (Neurotrophin) and CDH5 (Cadherin 5) pathways predominate in rheumatoid arthritis, with a central role for THY1 (Thy-1 cell surface antigen) CDH11 (Cadherin 11) cells. The OA opens the PDGF (Platelet-derived growth factors) pathway (driver of bone angiogenesis), the RA opens the EGF pathway (bone formation) and the SEMA3 (Semaphorin 3A) pathway (involved in immune regulation). Interestingly, we found that OA no longer has cell types involved in the MHC complex (Major histocompatibility complex) and their activity, whereas the MHC complex functions primarily in RA in the presentation of inflammatory antigens, and that the complement system in OA has the potential to displace the function of the MHC complex. The specific signaling patterns of THY1CDH11 cells and their secreted ligand receptors are more conducive to cell migration and lay the foundation for promoting osteoclastogenesis. This subpopulation may also be involved in the accumulation of lymphocytes, affecting the recruitment of immune cells. Members of the collagen family (COL1A1 (Collagen Type I Alpha 1 Chain), COL6A2 (Collagen Type VI Alpha 2 Chain) and COL6A1 (Collagen Type VI Alpha 1 Chain)) and transforming growth factor (TGFB3) maintain the extracellular matrix in osteoarthritis and mediate cell migration and adhesion in rheumatoid arthritis, including the PTN (Pleiotrophin) / THBS1 (Thrombospondin 1) interaction.
CONCLUSION
Increased understanding of the interaction networks between synovial fibroblast subtypes, particularly the shared and unique cellular communication features between osteoarthritis and rheumatoid arthritis and their hub cells, should help inform the design of therapeutic agents for inflammatory joint disease.
Topics: Humans; Synovial Membrane; Epidermal Growth Factor; Laminin; Collagen Type VI; Arthritis, Rheumatoid; Osteoarthritis; Cell Communication; Fibroblasts; Communication
PubMed: 37704178
DOI: 10.1016/j.imlet.2023.09.005 -
Annals of the Rheumatic Diseases Dec 2023Transcriptomic profiling of synovial tissue from patients with early, untreated rheumatoid arthritis (RA) was used to explore the ability of unbiased, data-driven...
OBJECTIVES
Transcriptomic profiling of synovial tissue from patients with early, untreated rheumatoid arthritis (RA) was used to explore the ability of unbiased, data-driven approaches to define clinically relevant subgroups.
METHODS
RNASeq was performed on 74 samples, with disease activity data collected at inclusion. Principal components analysis (PCA) and unsupervised clustering were used to define patient clusters based on expression of the most variable genes, followed by pathway analysis and inference of relative abundance of immune cell subsets. Histological assessment and multiplex immunofluorescence (for CD45, CD68, CD206) were performed on paraffin sections.
RESULTS
PCA on expression of the (n=894) most variable genes across this series did not divide samples into distinct groups, instead yielding a continuum correlated with baseline disease activity. Two patient clusters (PtC1, n=52; PtC2, n=22) were defined based on expression of these genes. PtC1, with significantly higher disease activity and probability of response to methotrexate therapy, showed upregulation of immune system genes; PtC2 showed upregulation of lipid metabolism genes, described to characterise tissue resident or M2-like macrophages. In keeping with these data, M2-like:M1-like macrophage ratios were inversely correlated with disease activity scores and were associated with lower synovial immune infiltration and the presence of thinner, M2-like macrophage-rich synovial lining layers.
CONCLUSION
In this large series of early, untreated RA, we show that the synovial transcriptome closely mirrors clinical disease activity and correlates with synovial inflammation. Intriguingly, lower inflammation and disease activity are associated with higher ratios of M2:M1 macrophages, particularly striking in the synovial lining layer. This may point to a protective role for tissue resident macrophages in RA.
Topics: Humans; Transcriptome; Synovitis; Arthritis, Rheumatoid; Synovial Membrane; Inflammation
PubMed: 37507201
DOI: 10.1136/ard-2023-224068 -
Biochemical and Biophysical Research... Aug 2023Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease. Recently, NLRP3 has been demonstrated to be closely related to RA. The objective of our research...
Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease. Recently, NLRP3 has been demonstrated to be closely related to RA. The objective of our research was to analyze the specific mechanism of NLRP3 in RA. The m6A levels of NLRP3 was detected with methylated RNA immunoprecipitation (MeRIP) kit. The mRNA and protein levels of related genes were tested with RT-qPCR and Western blot. The inflammatory factors levels were detected with ELISA kits. The cell proliferative ability was measured with CCK-8 and EdU staining assays. NLRP3 levels was prominently in synovial tissues and fibroblast-like synoviocytes (FLS) from RA patients. NLRP3 silencing suppressed FLS proliferation and inflammatory factor levels. Additionally, ALKBH5 was found to bind with NLRP3, and ALKBH5 silencing suppressed FLS proliferation and inflammatory factor levels while NLRP3 overexpressing neutralized the role of ALKBH5 in FLS. Furthermore, m6A modified induced by ALKBH5 suppressed NLRP3 mRNA level through YTHDC2 in RA, and NLRP3 is a hinge factor in RA progression.
Topics: Humans; NLR Family, Pyrin Domain-Containing 3 Protein; Arthritis, Rheumatoid; Synovial Membrane; Synoviocytes; Transcription Factors; Cell Proliferation; Fibroblasts; Cells, Cultured; AlkB Homolog 5, RNA Demethylase; RNA-Binding Proteins
PubMed: 37244037
DOI: 10.1016/j.bbrc.2023.05.087 -
Nature Communications Feb 2024Frozen shoulder is a spontaneously self-resolving chronic inflammatory fibrotic human disease, which distinguishes the condition from most fibrotic diseases that are...
Frozen shoulder is a spontaneously self-resolving chronic inflammatory fibrotic human disease, which distinguishes the condition from most fibrotic diseases that are progressive and irreversible. Using single-cell analysis, we identify pro-inflammatory MERTKCD48 macrophages and MERTK + LYVE1 + MRC1+ macrophages enriched for negative regulators of inflammation which co-exist in frozen shoulder capsule tissues. Micro-cultures of patient-derived cells identify integrin-mediated cell-matrix interactions between MERTK+ macrophages and pro-resolving DKK3+ and POSTN+ fibroblasts, suggesting that matrix remodelling plays a role in frozen shoulder resolution. Cross-tissue analysis reveals a shared gene expression cassette between shoulder capsule MERTK+ macrophages and a respective population enriched in synovial tissues of rheumatoid arthritis patients in disease remission, supporting the concept that MERTK+ macrophages mediate resolution of inflammation and fibrosis. Single-cell transcriptomic profiling and spatial analysis of human foetal shoulder tissues identify MERTK + LYVE1 + MRC1+ macrophages and DKK3+ and POSTN+ fibroblast populations analogous to those in frozen shoulder, suggesting that the template to resolve fibrosis is established during shoulder development. Crosstalk between MerTK+ macrophages and pro-resolving DKK3+ and POSTN+ fibroblasts could facilitate resolution of frozen shoulder, providing a basis for potential therapeutic resolution of persistent fibrotic diseases.
Topics: Humans; c-Mer Tyrosine Kinase; Bursitis; Inflammation; Synovial Membrane; Fibrosis
PubMed: 38374174
DOI: 10.1038/s41467-024-45341-9 -
Journal of Orthopaedic Research :... Jan 2024Periprosthetic joint infection (PJI) is a major complication of total joint arthroplasty. Even with current treatments, failure rates are unacceptably high with a 5-year... (Review)
Review
Periprosthetic joint infection (PJI) is a major complication of total joint arthroplasty. Even with current treatments, failure rates are unacceptably high with a 5-year mortality rate of 26%. Majority of the literature in the field has focused on development of better biomarkers for diagnostics and treatment strategies including innovate antibiotic delivery systems, antibiofilm agents, and bacteriophages. Nevertheless, the role of the immune system, our first line of defense during PJI, is not well understood. Evidence of infection in PJI patients is found within circulation, synovial fluid, and tissue and include numerous cytokines, metabolites, antimicrobial peptides, and soluble receptors that are part of the PJI diagnosis workup. Macrophages, neutrophils, and myeloid-derived suppressor cells (MDSCs) are initially recruited into the joint by chemokines and cytokines produced by immune cells and bacteria and are activated by pathogen-associated molecular patterns. While these cells are efficient killers of planktonic bacteria by phagocytosis, opsonization, degranulation, and recruitment of adaptive immune cells, biofilm-associated bacteria are troublesome. Biofilm is not only a physical barrier for the immune system but also elicits effector functions. Additionally, bacteria have developed mechanisms to evade the immune system by inactivating effector molecules, promoting killing or anti-inflammatory effector cell phenotypes, and intracellular persistence and dissemination. Understanding these shortcomings and the mechanisms by which bacteria can subvert the immune system may open new approaches to better prepare our own immune system to combat PJI. Furthermore, preoperative immune system assessment and screening for dysregulation may aid in developing preventative interventions to decrease PJI incidence.
Topics: Humans; Prosthesis-Related Infections; Anti-Bacterial Agents; Biofilms; Arthritis, Infectious; Biomarkers; Cytokines; Bacteria; Synovial Fluid
PubMed: 37874328
DOI: 10.1002/jor.25723 -
Annales D'endocrinologie Jun 2024Osteoarthritis (OA) is the most common musculoskeletal disease, without any curative treatment. Obesity being the main modifiable risk factor for OA, much attention... (Review)
Review
Osteoarthritis (OA) is the most common musculoskeletal disease, without any curative treatment. Obesity being the main modifiable risk factor for OA, much attention focused on the role of adipose tissues (AT). In addition to the involvement of visceral and subcutaneous AT via systemic ways, many arguments also highlight the involvement of local AT, present in joint tissues. Local AT include intra-articular AT (IAAT), which border the synovium, and bone marrow AT (BMAT) localized within marrow cavities in the bones. This review describes the known features and involvement of IAAT and BMAT in joint homeostasis and OA. Recent findings evidence that alteration in magnetic resonance imaging signal intensity of infrapatellar fat pad can be predictive of the development and progression of knee OA. IAAT and synovium are partners of the same functional unit; IAAT playing an early and pivotal role in synovial inflammation and fibrosis and OA pain. BMAT, whose functions have only recently begun to be studied, is in close functional interaction with its microenvironment. The volume and molecular profile of BMAT change according to the pathophysiological context, enabling fine regulation of haematopoiesis and bone metabolism. Although its role in OA has not yet been studied, the localization of BMAT, its functions and the importance of the bone remodelling processes that occur in OA argue in favour of a role for BMAT in OA.
Topics: Humans; Adipose Tissue; Osteoarthritis; Synovial Membrane; Joints; Osteoarthritis, Knee; Obesity; Bone Marrow; Magnetic Resonance Imaging; Animals
PubMed: 38871517
DOI: 10.1016/j.ando.2024.05.012 -
Nature Reviews. Rheumatology May 2024In rheumatoid arthritis, juvenile idiopathic arthritis and other forms of inflammatory arthritis, the immune system targets certain joints but not others. The pattern of... (Review)
Review
In rheumatoid arthritis, juvenile idiopathic arthritis and other forms of inflammatory arthritis, the immune system targets certain joints but not others. The pattern of joints affected varies by disease and by individual, with flares most commonly involving joints that were previously inflamed. This phenomenon, termed joint-specific memory, is difficult to explain by systemic immunity alone. Mechanisms of joint-specific memory include the involvement of synovial resident memory T cells that remain in the joint during remission and initiate localized disease recurrence. In addition, arthritis-induced durable changes in synovial fibroblasts and macrophages can amplify inflammation in a site-specific manner. Together with ongoing systemic processes that promote extension of arthritis to new joints, these local factors set the stage for a stepwise progression in disease severity, a paradigm for arthritis chronicity that we term the joint accumulation model. Although durable drug-free remission through early treatment remains elusive for most forms of arthritis, the joint accumulation paradigm defines new therapeutic targets, emphasizes the importance of sustained treatment to prevent disease extension to new joints, and identifies a rolling window of opportunity for altering the natural history of arthritis that extends well beyond the initiation phase of disease.
Topics: Humans; Memory T Cells; Arthritis, Rheumatoid; Joints; Immunologic Memory; Disease Progression; Animals; Synovial Membrane; Arthritis
PubMed: 38600215
DOI: 10.1038/s41584-024-01107-7 -
Arthritis & Rheumatology (Hoboken, N.J.) Mar 2024Recent studies have uncovered diverse cell types and states in the rheumatoid arthritis (RA) synovium; however, limited data exist correlating these findings with...
OBJECTIVE
Recent studies have uncovered diverse cell types and states in the rheumatoid arthritis (RA) synovium; however, limited data exist correlating these findings with patient-level clinical information. Using the largest cohort to date with clinical and multicell data, we determined associations between RA clinical factors with cell types and states in the RA synovium.
METHODS
The Accelerated Medicines Partnership Rheumatoid Arthritis study recruited patients with active RA who were not receiving disease-modifying antirheumatic drugs (DMARDs) or who had an inadequate response to methotrexate (MTX) or tumor necrosis factor inhibitors. RA clinical factors were systematically collected. Biopsies were performed on an inflamed joint, and tissue were disaggregated and processed with a cellular indexing of transcriptomes and epitopes sequencing pipeline from which the following cell type percentages and cell type abundance phenotypes (CTAPs) were derived: endothelial, fibroblast, and myeloid (EFM); fibroblasts; myeloid; T and B cells; T cells and fibroblasts (TF); and T and myeloid cells. Correlations were measured between RA clinical factors, cell type percentage, and CTAPs.
RESULTS
We studied 72 patients (mean age 57 years, 75% women, 83% seropositive, mean RA duration 6.6 years, mean Disease Activity Score-28 C-reactive Protein 3 [DAS28-CRP3] score 4.8). Higher DAS28-CRP3 correlated with a higher T cell percentage (P < 0.01). Those receiving MTX and not a biologic DMARD (bDMARD) had a higher percentage of B cells versus those receiving no DMARDs (P < 0.01). Most of those receiving bDMARDs were categorized as EFM (57%), whereas none were TF. No significant difference was observed across CTAPs for age, sex, RA disease duration, or DAS28-CRP3.
CONCLUSION
In this comprehensive screen of clinical factors, we observed differential associations between DMARDs and cell phenotypes, suggesting that RA therapies, more than other clinical factors, may impact cell type/state in the synovium and ultimately influence response to subsequent therapies.
Topics: Humans; Female; Middle Aged; Male; Antirheumatic Agents; Methotrexate; Arthritis, Rheumatoid; Synovial Membrane; Rheumatoid Factor
PubMed: 37791989
DOI: 10.1002/art.42726 -
Nature Communications Mar 2024Inflammatory arthritis (IA) is a common rheumatic adverse event following immune checkpoint inhibitors treatment. The clinical disparities between IA and rheumatoid...
Inflammatory arthritis (IA) is a common rheumatic adverse event following immune checkpoint inhibitors treatment. The clinical disparities between IA and rheumatoid arthritis (RA) imply disease heterogeneity and distinct mechanisms, which remain elusive. Here, we profile CD45 cells from the peripheral blood or synovial fluid (SF) of patients with PD-1-induced IA (PD-1-IA) or RA using single-cell RNA sequencing. We report the predominant expansion of IL1B myeloid cells with enhanced NLRP3 inflammasome activity, in both the SF and peripheral blood of PD-1-IA, but not RA. IL1B macrophages in the SF of PD-1-IA shared similar inflammatory signatures and might originate from peripheral IL1B monocytes. Exhausted CD8 T cells (Texs) significantly accumulated in the SF of patients with PD-1-IA. IL1B myeloid cells communicated with CD8 Texs possibly via the CCR1-CCL5/CCL3 and CXCL10-CXCR3 axes. Collectively, these results demonstrate different cellular and molecular pathways in PD-1-IA and RA and highlight IL1B macrophages as a possible therapeutic target in PD-1-IA.
Topics: Humans; Immune Checkpoint Inhibitors; CD8-Positive T-Lymphocytes; Programmed Cell Death 1 Receptor; Arthritis, Rheumatoid; Inflammation; Macrophages; Synovial Fluid; Interleukin-1beta
PubMed: 38453911
DOI: 10.1038/s41467-024-46195-x -
International Journal of Molecular... Jul 2023Osteoarthritis (OA) is a multifactorial disease in which genetics, aging, obesity, and trauma are well-known risk factors. It is the most prevalent joint disease and the... (Review)
Review
Osteoarthritis (OA) is a multifactorial disease in which genetics, aging, obesity, and trauma are well-known risk factors. It is the most prevalent joint disease and the largest disability problem worldwide. Recent findings have described the role of damage-associated molecular patterns (DAMPs) in the course of the disease. In particular, alarmins such as HMGB1, IL-33, and S100B, appear implicated in enhancing articular inflammation and favouring a catabolic switch in OA chondrocytes. The aims of this review are to clarify the molecular signalling of these three molecules in OA pathogenesis, to identify their possible use as staging biomarkers, and, most importantly, to find out whether they could be possible therapeutic targets. Osteoarthritic cartilage expresses increased levels of all three alarmins. HMGB1, in particular, is the most studied alarmin with increased levels in cartilage, synovium, and synovial fluid of OA patients. High levels of HMGB1 in synovial fluid of OA joints are positively correlated with radiological and clinical severity. Counteracting HMGB1 strategies have revealed improving results in articular cells from OA patients and in OA animal models. Therefore, drugs against this alarmin, such as anti-HMGB1 antibodies, could be new treatment possibilities that can modify the disease course since available medications only alleviate symptoms.
Topics: Animals; Alarmins; Cartilage, Articular; Chondrocytes; HMGB1 Protein; Interleukin-33; Joints; Osteoarthritis; Synovial Membrane
PubMed: 37569519
DOI: 10.3390/ijms241512143