Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
Key Laboratory of the Ministry of Education for Medicinal Resources and Natural Pharmaceutical Chemistry, College of Life Sciences, Shanxi Normal University, Xi'an, China.
Brain Behav Immun. 2018 Feb;68:44-55. doi: 10.1016/j.bbi.2017.09.015. Epub 2017 Sep 27.
Nuclear receptor4 group A1 (Nr4a1), an orphan nuclear receptor, is down-regulated in peripheral blood mononuclear cells (MNCs) of individuals with multiple sclerosis (MS), and Nr4a1 deficiency results in severe experimental autoimmune encephalomyelitis (EAE), an animal model of MS, caused by increased macrophage infiltration into the central nervous system (CNS). However, the role of Nr4a1 in macrophage phenotype and T cell responses remains poorly understood. In the present study we show that macrophages/microglia of Nr4a1 mice, which exhibited earlier onset and more severe clinical EAE, were polarized to an enhanced type 1 (M1) phenotype and produced higher levels of IL-12 and TNF-α than wild type mice. Significantly increased numbers of CD4 T cells and frequency of CD4IFN-γ and CD4IL-17 T cells were observed in the CNS and spleen of Nr4a1 mice, with decreased percentages of apoptosis in CD4 T cells. The percentages of CD4Foxp3 Treg cells in the CNS of Nr4a1 mice were also reduced. Furthermore, purified CD4 T cells from naïve Nr4a1 mice exhibited enhanced Th1 and Th17 differentiation capacity, and MOG-reactive Th17 cells from Nr4a1 mice adoptively transferred more severe EAE in recipient mice. Our results, for the first time, demonstrate that Nr4a1 not only induces Type 2 macrophages/microglia phenotype, but is also a critical inhibitory molecule for Th1/Th17 cell differentiation. This finding indicates that Nr4a1-related molecule(s) may have therapeutic potential in MS and likely other autoimmune disorders.
核受体 4 组 A1（Nr4a1）是一种孤儿核受体，在多发性硬化症（MS）患者的外周血单核细胞（MNC）中下调，而 Nr4a1 缺乏导致严重的实验性自身免疫性脑脊髓炎（EAE），这是 MS 的动物模型，其原因是巨噬细胞浸润中枢神经系统（CNS）增加。然而，Nr4a1 在巨噬细胞表型和 T 细胞反应中的作用仍知之甚少。在本研究中，我们发现 Nr4a1 小鼠的巨噬细胞/小胶质细胞表现出更早发病和更严重的临床 EAE，其极化表现为增强的 1 型（M1）表型，并且比野生型小鼠产生更高水平的 IL-12 和 TNF-α。Nr4a1 小鼠的中枢神经系统和脾脏中观察到 CD4 T 细胞数量显著增加，CD4IFN-γ 和 CD4IL-17 T 细胞的频率增加，而 CD4 T 细胞的凋亡百分比降低。Nr4a1 小鼠中枢神经系统中的 CD4Foxp3 Treg 细胞的百分比也降低。此外，来自幼稚 Nr4a1 小鼠的纯化 CD4 T 细胞表现出增强的 Th1 和 Th17 分化能力，并且来自 Nr4a1 小鼠的 MOG 反应性 Th17 细胞在受者小鼠中传递更严重的 EAE。我们的研究结果首次表明，Nr4a1 不仅诱导 2 型巨噬细胞/小胶质细胞表型，而且还是 Th1/Th17 细胞分化的关键抑制分子。这一发现表明，Nr4a1 相关分子在 MS 及可能的其他自身免疫性疾病中具有治疗潜力。
