Cytokine Balance in Rheumatoid Arthritis

炎性细胞因子在类风湿关节炎(RA)滑膜(关节)病理中的一个重要作用是 已被证实，并已被成功地靶向治疗肿瘤坏死因子和白介素6所验证。炎症性 细胞因子通过激活滑膜中的细胞和诱导免疫细胞的募集来推动RA的发病。 该项目的长期目标是了解炎性细胞因子在RA中的作用 病机激活巨噬细胞，这是一种重要的致病细胞类型。一个相关的目标是识别小说 调节巨噬细胞炎症表型的细胞因子介导的通路可作为靶点 抑制类风湿关节炎发病的新治疗方法。 肿瘤坏死因子是类风湿关节炎的主要致病细胞因子和强烈的炎症反应激活剂。古典主义 肿瘤坏死因子对细胞的炎症激活是由典型的NF-B信号介导的，该信号激活众所周知 肿瘤坏死因子以IL-1和IL-6等基因为靶标。在之前的项目期间，我们使用了信号传递和转录 研究肿瘤坏死因子激活的人类新途径和基因表达模式的方法 巨噬细胞。我们发现，肿瘤坏死因子诱导了延迟但持续的非规范的NF-B、JAK和AP-1信号转导 这导致了转录因子的激活，包括STAT3，而这些转录因子并不是肿瘤坏死因子的一部分 回应。这些转录因子激活了晚期肿瘤坏死因子诱导的基因表达，目前还没有 希望成为肿瘤坏死因子的靶点。这些基因包括炎症信号的反馈抑制物，以及 可能在炎症加速的动脉粥样硬化中起重要作用的脂代谢介质。后期 肿瘤坏死因子诱导的基因在RA滑膜巨噬细胞中表达，提示这些基因与滑膜炎有关。 RA滑膜的特点是低氧压(低氧)和伴随的细胞糖酵解 代谢和代谢应激。滑膜缺氧在关节炎发病机制中的重要性 越来越受人赞赏。我们发现缺氧重塑了人类晚期的肿瘤坏死因子反应 巨噬细胞，包括STAT3依赖基因的减弱和脂代谢基因的抑制。 这些基因的表达依赖于主要代谢调节因子mTORC1和低氧 至少部分通过抑制mTORC1活性来下调基因表达。这些结果表明了新的 缺氧和代谢应激调节类风湿关节炎滑膜炎症反应的机制。 基于我们的总体假设，晚期肿瘤坏死因子信号和基因表达，及其 低氧和代谢应激的调节，有助于RA的发病，我们将探讨其机制 晚期肿瘤坏死因子反应的基础，缺氧对其调节，以及它们在 巨噬细胞炎症表型、关节炎和炎症加速的动脉粥样硬化。我们期待着 这些研究将揭示炎性巨噬细胞调控的新途径 表型，从而为RA的治疗干预确定新的靶点。

An important role for inflammatory cytokines in driving synovial (joint) pathology in rheumatoid arthritis (RA) is well established and has been validated by the success of therapeutic targeting of TNF and IL-6. Inflammatory cytokines drive RA pathogenesis by activating cells in the synovium and inducing recruitment of immune cells. The long term goals of this project are to understand how inflammatory cytokines implicated in RA pathogenesis activate macrophages, an important pathogenic cell type. An associated goal is to identify novel cytokine-mediated pathways that regulate macrophage inflammatory phenotype that can serve as targets for new therapeutic approaches to suppress RA pathogenesis. TNF is a major pathogenic cytokine in RA and a strong activator of inflammatory responses. Classical inflammatory activation of cells by TNF is mediated by canonical NF-B signaling that activates well known TNF target genes such as IL-1 and IL-6. In the previous project period, we used signaling and transcriptomic approaches to investigate novel pathways and gene expression patterns activated by TNF in human macrophages. We found that TNF induced delayed but sustained noncanonical NF-B, Jak and AP-1 signaling that resulted in activation of transcription factors, including STAT3, that are not known to be part of the TNF response. These transcription factors activated expression of late phase TNF-induced genes not currently appreciated to be TNF targets. These genes included feedback inhibitors of inflammatory signaling, and mediators of lipid metabolism that may be important for inflammation-accelerated atherosclerosis. Late phase TNF-induced genes were expressed in RA synovial macrophages, implicating these genes in synovitis. RA synovium is characterized by low oxygen tension (hypoxia) and associated cellular glycolytic metabolism and metabolic stress. The importance of synovial hypoxia in arthritis pathogenesis is becoming increasingly appreciated. We found that hypoxia remodels the late phase TNF response in human macrophages, including attenuation of STAT3-dependent genes and suppression of lipid metabolism genes. Expression of these genes was dependent on the master metabolic regulator mTORC1, and hypoxia downregulated gene expression at least in part by suppressing mTORC1 activity. These results suggest novel mechanisms by which hypoxia and metabolic stress modulate inflammatory responses in RA synovium. Based on our overarching hypothesis that late phase TNF signaling and gene expression, and its regulation by hypoxia and metabolic stress, contribute to RA pathogenesis, we will investigate mechanisms underlying the late phase TNF response, its regulation by hypoxia, and their functional importance for macrophage inflammatory phenotype, arthritis, and inflammation-accelerated atherosclerosis. We anticipate that these studies will reveal new pathways important in the regulation of inflammatory macrophage phenotype, and thus identify new targets for therapeutic intervention in RA.