LAT1-specific inhibitor ameliorates severe autoimmune arthritis in SKG mouse
LAT1-specific inhibitor ameliorates severe autoimmune arthritis in SKG mouse
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DOI：
10.1016/j.intimp.2022.108817
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发表时间：
2022-05-11
影响因子：
5.6
通讯作者：
Hayashi, Keitaro
中科院分区：
文献类型：
--
作者：
Owada, Takayoshi;Kurasawa, Kazuhiro;Hayashi, Keitaro
L型氨基酸转运蛋白1（LAT 1，slc 7a 5）为高度增殖的细胞提供大量中性氨基酸。由于LAT 1在活化的T细胞中高表达，而在静息T细胞中不高表达，因此LAT 1是用于治疗过度活化的T细胞介导的免疫病症的有吸引力的治疗靶标。在这里，我们证明，LAT 1起着至关重要的作用，辅助性T细胞（Th）17介导的自身免疫性关节炎在SKG小鼠，人类类风湿性关节炎（RA）的动物模型。LAT 1特异性抑制剂JPH 203的给药抑制了SKG小鼠中甘露聚糖诱导的关节肿胀、滑膜细胞增殖和炎性细胞浸润。减少代谢重编程，包括减少氧化磷酸化，调节HIF-1 α的表达和糖酵解酶的后续控制，参与了通过LAT 1抑制下调Th 17分化。此外，公开发布的数据库分析显示，在RA患者中，LAT 1在具有细胞毒性特征的T细胞中促进表达。我们的研究结果证明了LAT 1对RA发展的重要贡献，提出了一种潜在的治疗方法，靶向氨基酸转运蛋白用于治疗过敏性免疫疾病。
L-type amino acid transporter 1 (LAT1, slc7a5) supplies large neutral amino acids to highly proliferative cells. LAT1 is an attractive therapeutic target for treating overactive T cell-mediated immune disorders due to its high expression in activated T cells, but not in resting T cells. Here, we demonstrate that LAT1 plays a crucial role in T helper (Th) 17-mediated autoimmune arthritis in SKG mice, an animal model of human rheumatoid arthritis (RA). Administration of JPH203, a LAT1-specific inhibitor, suppressed mannan-induced joint swelling, synoviocyte proliferation and inflammatory cell infiltration in SKG mice. A diminished metabolic reprogramming, including a decrease in oxidative phosphorylation that regulates Hif-1 alpha expression and subsequent control of glycolysis enzymes, was involved in the downregulation of Th17 differentiation by LAT1 inhibition. Moreover, publicly released database analysis revealed facilitated expression of LAT1 in T cells with cytotoxic features in patients with RA. Our results demonstrate the essential contribution of LAT1 to the development of RA, proposing a potential therapeutic approach targeting amino acid transporters for treating hypersensitive immune diseases.