Autoimmune uveitis (AU) is a severe disorder causing poor vision and blindness. However, the cellular dynamics and pathogenic mechanisms underlying retinal injury in uveitis remain unclear. In this study, single-cell RNA sequencing of the retina and cervical draining lymph nodes in experimental autoimmune uveitis mice was conducted to identify the cellular spatiotemporal dynamics and upregulation of the glycolysis-related gene LDHA. Suppression of LDHA can rescue the imbalance of T effector (Teff) cells/T regulator (Treg) cells under inflammation downregulation of the glycolysis-PI3K signaling circuit and inhibition of the migration of CXCR4 Teff cells towards retinal tissue. Furthermore, LDHA and CXCR4 are upregulated in the peripheral blood mononuclear cells of Vogt-Koyanagi-Harada patients. The LDHA inhibitor suppresses CD4 T cell proliferation in humans. Therefore, our data indicate that the autoimmune environment of uveitis regulates Teff cell accumulation in the retina glycolysis-associated LDHA. Modulation of this target may provide a novel therapeutic strategy for treating AU.

中文翻译：

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视网膜单细胞测序表明 LDHA 调节自身免疫性葡萄膜炎的发病机制

自身免疫性葡萄膜炎（AU）是一种严重的疾病，会导致视力不佳和失明。然而，葡萄膜炎视网膜损伤的细胞动力学和致病机制仍不清楚。在这项研究中，对实验性自身免疫性葡萄膜炎小鼠的视网膜和颈部引流淋巴结进行了单细胞RNA测序，以鉴定细胞时空动态和糖酵解相关基因LDHA的上调。抑制 LDHA 可以挽救炎症下调糖酵解-PI3K 信号通路和抑制 CXCR4 Teff 细胞向视网膜组织迁移的情况下 T 效应 (Teff) 细胞/T 调节 (Treg) 细胞的不平衡。此外，Vogt-Koyanagi-Harada 患者的外周血单核细胞中 LDHA 和 CXCR4 上调。 LDHA 抑制剂可抑制人类 CD4 T 细胞增殖。因此，我们的数据表明葡萄膜炎的自身免疫环境调节视网膜糖酵解相关的 LDHA 中 Teff 细胞的积累。对该靶标的调节可能为治疗 AU 提供新的治疗策略。