Iron-dependent epigenetic modulation promotes pathogenic T cell differentiation in lupus.
Iron-dependent epigenetic modulation promotes pathogenic T cell differentiation in lupus.
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铁依赖性表观遗传调节促进狼疮致病性 T 细胞分化
DOI：
10.1172/jci152345
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发表时间：
2022-05-02
影响因子：
15.9
通讯作者：
Zhao, Ming
中科院分区：
文献类型：
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作者：
Gao, Xiaofei;Song, Yang;Wu, Jiali;Lu, Shuang;Min, Xiaoli;Liu, Limin;Hu, Longyuan;Zheng, Meiling;Du, Pei;Yu, Yaqin;Long, Hai;Wu, Haijing;Jia, Sujie;Yu, Di;Lu, Qianjin;Zhao, Ming
微量元素铁影响免疫反应和疫苗接种，但其在自身免疫性疾病中的作用的知识有限。系统性红斑狼疮（SLE）患者外周血T淋巴细胞尤其是辅助性T淋巴细胞（Tfh）的扩增在SLE发病中具有重要意义。在这里，我们表明铁在调节SLE致病性T细胞分化中的重要作用。我们发现，铁超载促进Tfh细胞扩增，促炎细胞因子分泌，并在狼疮易感小鼠自身抗体的生产。用高铁饮食处理的小鼠表现出Tfh细胞和抗原特异性GC反应的比例增加。铁的补充有助于Tfh细胞的分化。相反，铁螯合抑制Tfh细胞分化。我们证明miR-21/BDH 2轴在Tfh细胞分化过程中驱动铁积累，并进一步促进Fe 2+依赖性泰特酶活性和BCL 6基因去甲基化。因此，维持铁稳态可能是消除致病性Th细胞的关键，并可能有助于改善SLE患者的管理。
The trace element iron affects immune responses and vaccination, but knowledge of its role in autoimmune diseases is limited. Expansion of pathogenic T cells, especially T follicular helper (Tfh) cells, has great significance to systemic lupus erythematosus (SLE) pathogenesis. Here, we show an important role of iron in regulation of pathogenic T cell differentiation in SLE. We found that iron overload promoted Tfh cell expansion, proinflammatory cytokine secretion, and autoantibody production in lupus-prone mice. Mice treated with a high-iron diet exhibited an increased proportion of Tfh cell and antigen-specific GC response. Iron supplementation contributed to Tfh cell differentiation. In contrast, iron chelation inhibited Tfh cell differentiation. We demonstrated that the miR-21/BDH2 axis drove iron accumulation during Tfh cell differentiation and further promoted Fe2+-dependent TET enzyme activity and BCL6 gene demethylation. Thus, maintaining iron homeostasis might be critical for eliminating pathogenic Th cells and might help improve the management of patients with SLE.