Murphy Evelyn P, Crean Daniel
School of Medicine, University of Limerick, Limerick, Ireland.
School of Veterinary Medicine, University College Dublin, Dublin, Ireland.
Front Med (Lausanne). 2022 Jul 22;9:874182. doi: 10.3389/fmed.2022.874182. eCollection 2022.
The development and progression of immune-mediated rheumatic disease (IMRD) involves dysfunction of innate and adaptive immune cell populations leading to altered responses including inflammasome activation, dysregulated cytokine networks, increased immune cell numbers and multifaceted cell-cell communication. Several rheumatic diseases are further characterized by the presence of autoantibodies, immune complex mediated complement activation and the deficit of peripheral immune tolerance due to reduced regulatory T-lymphocyte cell function. Ultimately, in rheumatic disease the loss in cellular and tissue homeostasis culminates in the advancement of chronic inflammation. The three members of the NR4A subfamily of nuclear receptors are immediate early genes, and act as potent transcriptional responders to changes in the cellular and tissue microenvironment. Subfamily members are rapidly expressed in diseases characterized by inflammation and function to control the differentiation and activity of innate and adaptive immune cells in a cell-type and cell-context specific manner. Rheumatic disease including rheumatoid-, psoriatic-, osteo-arthritis and systemic sclerosis display altered NR4A1-3 activity in controlling immune cell migration and function, production of paracrine signaling molecules, synovial tissue hyperplasia, and regulating cartilage turn-over . Additionally, NR4A1-3 activities mediate cytokine, prostanoid and growth factor signaling to control angiogenesis, modulate the regulatory functions of mesenchymal stromal cells, alter the activation status of dendritic cells, influence the generation of peripheral myeloid and T-lymphocyte lineages and promote the maintenance of functional regulatory T-cells. Further reports uncover the potential of moderating NR4A 1-3 receptors as therapeutic targets in altering immune tolerance, pathological angiogenesis and controlling inflammation in several models of disease.
免疫介导的风湿性疾病（IMRD）的发生和发展涉及先天性和适应性免疫细胞群功能障碍，导致反应改变，包括炎性小体激活、细胞因子网络失调、免疫细胞数量增加以及多方面的细胞间通讯。几种风湿性疾病的进一步特征是存在自身抗体、免疫复合物介导的补体激活以及由于调节性T淋巴细胞功能降低导致的外周免疫耐受缺陷。最终，在风湿性疾病中，细胞和组织稳态的丧失最终导致慢性炎症的进展。核受体NR4A亚家族的三个成员是即早基因，并作为细胞和组织微环境变化的有效转录应答者。亚家族成员在以炎症为特征的疾病中迅速表达，并以细胞类型和细胞背景特异性方式控制先天性和适应性免疫细胞的分化和活性。包括类风湿性关节炎、银屑病关节炎、骨关节炎和系统性硬化症在内的风湿性疾病在控制免疫细胞迁移和功能、旁分泌信号分子的产生、滑膜组织增生以及调节软骨周转方面显示出NR4A1-3活性改变。此外，NR4A1-3活性介导细胞因子、前列腺素和生长因子信号传导，以控制血管生成、调节间充质基质细胞的调节功能、改变树突状细胞的激活状态、影响外周髓系和T淋巴细胞谱系的生成并促进功能性调节性T细胞的维持。进一步的报道揭示了在几种疾病模型中调节NR4A 1-3受体作为治疗靶点在改变免疫耐受、病理性血管生成和控制炎症方面的潜力。
