Cytokine regulation of RA synoviocyte phenotype

RA滑膜细胞表型的细胞因子调节

• 批准号: 10624310
• 负责人: Lionel B Ivashkiv
• 金额: $ 39.16万
• 依托单位: HOSPITAL FOR SPECIAL SURGERY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-27 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10624310
• 关键词: Acidosis; Adenosine; Anti-Inflammatory Agents; Antigen-Antibody Complex; Behavior; Biopsy; CSF3 gene; Cells; Chromatin; Chromatin Modeling; Coculture Techniques; Cyclic AMP; Cyclic AMP Receptors; DTR gene; Dinoprostone; Disease; Epigenetic Process; Equilibrium; Exhibits; Fibroblasts; G-Protein-Coupled Receptors; Gene Expression; Genes; Genetic Transcription; Goals; Growth Factor; Human; Immune; In Vitro; Inflammation; Inflammatory; Inflammatory Arthritis; Inflammatory Response; Interferons; Interleukin-1; Interleukin-6; Invaded; Joints; Knowledge; Lymphocyte; Macrophage; Macrophage Activation; Matrix Metalloproteinases; Mediating; Neuropeptides; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Phenotype; Process; Production; Property; Prostaglandins; Regulation; Regulatory Element; Rheumatoid Arthritis; Role; STAT4 gene; Signal Induction; Signal Pathway; Signal Transduction; Synovial Cell; Synovial Membrane; Synovitis; System; TNF gene; Testing; Therapeutic; Tissues; Treatment Efficacy; WFDC2 gene; autocrine; cell type; chemokine; cytokine; effective therapy; genetic signature; in vivo Model; joint inflammation; molecular modeling; novel therapeutics; programs; recruit; response; single-cell RNA sequencing; synergism; targeted treatment

In rheumatoid arthritis (RA) inflammatory cytokines produced by synovial (joint) cells drive disease pathogenesis by activating cells in inflamed joints and promoting recruitment of immune cells. The long-term goals of this project are to understand how cytokines and inflammatory factors expressed in RA synovium activate cells to drive disease pathogenesis, and to elucidate mechanisms that regulate production of pathogenic cytokines in the context of RA synovitis. An associated goal is to use this knowledge to develop safer and effective therapies that target disease-related mechanisms of cytokine production and function. This project has focused on two key synovial cell types important in RA pathogenesis, fibroblast-like synoviocytes (FLS) and synovial macrophages (Ms; previously termed type A synoviocytes). These two cell types interact closely in RA synovium. RA synovial macrophages express gene signatures reflecting inflammatory NF-B and Jak-STAT signaling and produce inflammatory cytokines. RA FLS produce cytokines and inflammatory factors such prostaglandins (PGs), and exhibit tissue-destructive properties. In the previous project period, we defined a role for FLS in regulating inflammatory M phenotype by modulating TNF responses to suppress IFN-stimulated gene (ISG) expression while promoting synergistic expression of inflammatory genes and growth factors that in turn increased FLS invasive behavior. A large fraction of the FLS-modulated TNF response in Ms was mediated by prostaglandin E2 (PGE2) and accordingly was almost completely recapitulated by exogenous PGE2, working via G protein- coupled receptors (GPCRs) and cAMP signaling. PGE2-cAMP signaling suppressed TNF and ISG expression, but cooperated with TNF to induce distinct inflammatory `synergy genes'. Strikingly, the gene signature commonly induced by FLS+TNF and PGE2+TNF was expressed in RA synovial macrophages, including a subset identified by single cell RNA sequencing that also expresses inflammatory and IFN signatures. These results highlight the importance of GPCR and downstream cAMP signaling in the RA synovial macrophage phenotype. GPCR-cAMP signaling in RA synovium can be activated by various factors including PGs, acidosis and neuropeptides. Thus, it is important to understand the impact of GPCR-cAMP signaling on macrophage inflammatory responses. Our overarching hypothesis is that the impact of PGE2- and GPCR-cAMP signaling on macrophage inflammatory responses can be selectively modulated to more effectively suppress TNF and ISGs, while avoiding induction of potentially pathogenic `synergy genes' such as those expressed by RA macrophages. In this project we will dissect signaling and chromatin-mediated mechanisms by which cAMP signaling regulates inflammatory responses in human macrophages. We anticipate that our studies will provide knowledge that can be used to shift GPCR-cAMP signaling towards increased suppression of inflammation.

在类风湿性关节炎（RA）炎症细胞因子产生滑膜（关节）细胞驱动疾病