Cytokine regulation of RA synoviocyte phenotype

RA滑膜细胞表型的细胞因子调节

• 批准号: 10449256
• 负责人: Lionel B Ivashkiv
• 金额: $ 38.77万
• 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/10449256
• 关键词: Acidosis; Adenosine; Anti-Inflammatory Agents; Antigen-Antibody Complex; Behavior; Biopsy; CSF3 gene; Cells; Chromatin; 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 Activation; Matrix Metalloproteinases; Mediating; Neuropeptides; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Phenotype; Process; Production; Property; Prostaglandins; Regulation; Regulatory Element; Rheumatoid Arthritis; Role; STAT4 gene; Signal Pathway; Signal Transduction; Synovial Cell; Synovial Membrane; Synovial joint; Synovitis; System; TNF gene; Testing; Therapeutic; Tissues; Treatment Efficacy; WFDC2 gene; autocrine; cell type; chemokine; chromatin remodeling; cytokine; effective therapy; genetic signature; in vivo Model; joint inflammation; macrophage; molecular modeling; novel therapeutics; 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）中，由滑膜（关节）细胞产生的炎性细胞因子驱动疾病 通过激活发炎关节中的细胞和促进免疫细胞的募集来治疗关节炎。长期 本研究的目的是了解细胞因子和炎症因子在RA滑膜中的表达 激活细胞以驱动疾病的发病机制，并阐明调节 RA滑膜炎背景下的致病性细胞因子。一个相关的目标是利用这些知识来开发 更安全和有效的疗法，针对疾病相关的细胞因子产生和功能机制。 该项目集中于两种在RA发病机制中重要的关键滑膜细胞类型，成纤维细胞样 滑膜细胞（FLS）和滑膜巨噬细胞（M细胞;以前称为A型滑膜细胞）。这两 细胞类型在RA滑膜中密切相互作用。RA滑膜巨噬细胞表达基因特征， 炎性NF-κ B B和Jak-STAT信号传导并产生炎性细胞因子。RA FLS生产 细胞因子和炎性因子，如前列腺素（PGs），并表现出组织破坏性。 在上一个项目期间，我们确定了FLS在调节炎症性M β细胞表型中的作用， 通过调节TNF应答以抑制IFN刺激的基因（ISG）表达，同时促进 炎症基因和生长因子的协同表达反过来增加了FLS的侵袭性， 行为在巨噬细胞中，FLS调节的TNF应答大部分是由前列腺素E2介导的 （PGE 2），因此几乎完全由外源性PGE 2重演，通过G蛋白- 偶联受体（GPCR）和cAMP信号传导。PGE 2-cAMP信号转导抑制TNF和ISG 表达，但与TNF合作，以诱导不同的炎症“协同基因”。 引人注目的是，FLS+TNF和PGE 2 +TNF共同诱导的基因标记在小鼠中表达， RA滑膜巨噬细胞，包括通过单细胞RNA测序鉴定的亚群，其也表达 炎症和IFN信号。这些结果突出了GPCR和下游cAMP的重要性。 RA滑膜巨噬细胞表型中的信号传导。RA滑膜中的GPCR-cAMP信号传导可以是 由各种因素激活，包括PG、酸中毒和神经肽。因此，重要的是要了解 GPCR-cAMP信号对巨噬细胞炎症反应的影响。 我们的总体假设是，PGE 2和GPCR-cAMP信号对巨噬细胞的影响， 可以选择性地调节炎症反应以更有效地抑制TNF和ISG， 避免诱导潜在致病的“协同基因”，如RA巨噬细胞表达的那些。 在这个项目中，我们将剖析信号和染色质介导的机制，cAMP信号 调节人类巨噬细胞中的炎症反应。我们预计我们的研究将提供 这些知识可用于将GPCR-cAMP信号传导转向增加炎症抑制。