Targeting L-type amino acid transporter 1 in innate and adaptive T cells efficiently controls skin inflammation
Targeting L-type amino acid transporter 1 in innate and adaptive T cells efficiently controls skin inflammation
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DOI：
10.1016/j.jaci.2019.09.025
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发表时间：
2020-01-01
影响因子：
14.2
通讯作者：
Sanchez-Madrid, Francisco
中科院分区：
文献类型：
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作者：
Cibrian, Danay;Castillo-Gonzalez, Raquel;Sanchez-Madrid, Francisco
背景：银屑病是一种常见的炎症性皮肤病，主要由IL-23、IL-1 β和IL-17细胞因子介导。虽然银屑病是一种过度增生性皮肤疾病，但氨基酸转运蛋白的可能作用尚未被探索。目的：我们试图研究必需氨基酸转运蛋白L型氨基酸转运蛋白（LAT）1（SLC 7A 5）在银屑病中的作用。在角蛋白5，CD 4，和视黄酸受体相关孤儿受体γ。我们制作了由咪喹莫特（IMQ）和IL-23诱导的皮肤炎症模型，并测试了抑制LAT 1（JPH 2 O3）和雷帕霉素哺乳动物靶蛋白（mTOR [雷帕霉素]）的效果。角质形成细胞中的LAT 1缺失不会抑制炎症反应或其增殖，这可以通过增加替代氨基酸转运蛋白LAT 2和LAT 3的表达来维持。γ δ和CD 4 T细胞中LAT 1的特异性缺失控制IMQ诱导的炎症反应LAT 1缺失或抑制阻断IL-17分泌γ 4（+）δ 4（+）和CD 4 T细胞的扩增，并抑制IMQ诱导模型中IL-1 β、IL-17和IL-22的释放。此外，LAT 1的抑制阻断人γ δ T细胞的扩增和人CD 4 T细胞的IL-17分泌。IL-23和IL-1 β刺激上调IL-17 + γ δ和T（H）17细胞中的LAT 1表达并诱导mTOR活化。LAT 1的缺失或抑制有效地控制IL-23-和IL-1 β诱导的磷脂酰肌醇3-激酶/AKT/mTOR激活独立于T细胞受体signaling.Conclusion：靶向LAT 1介导的氨基酸摄取是一种潜在有用的免疫抑制策略，以控制IL-23/IL-1 β/IL-17轴介导的皮肤炎症。
Background: Psoriasis is a frequent inflammatory skin disease that is mainly mediated by IL-23, IL-1 beta, and IL-17 cytokines. Although psoriasis is a hyperproliferative skin disorder, the possible role of amino acid transporters has remained unexplored.Objective: We sought to investigate the role of the essential amino acid transporter L-type amino acid transporter (LAT) 1 (SLC7A5) in psoriasis.Methods: LAT1 floxed mice were crossed to Cre-expressing mouse strains under the control of keratin 5, CD4, and retinoic acid receptor-related orphan receptor gamma. We produced models of skin inflammation induced by imiquimod (IMQ) and IL-23 and tested the effect of inhibiting LAT1 (JPH2O3) and mammalian target of rapamycin (mTOR [rapamycin]).Results: LAT1 expression is increased in keratinocytes and skin-infiltrating lymphocytes of psoriatic lesions in human subjects and mice. LAT1 deletion in keratinocytes does not dampen the inflammatory response or their proliferation, which could be maintained by increased expression of the alternative amino acid transporters LAT2 and LAT3. Specific deletion of LAT1 in gamma delta and CD4 T cells controls the inflammatory response induced by IMQ. LAT1 deletion or inhibition blocks expansion of IL-17-secreting gamma 4(+)delta 4(+) and CD4 T cells and dampens the release of IL-1 beta, IL-17, and IL-22 in the IMQ-induced model. Moreover, inhibition of LAT1 blocks expansion of human gamma delta T cells and IL-17 secretion by human CD4 T cells. IL-23 and IL-1 beta stimulation upregulates LAT1 expression and induces mTOR activation in IL-17 + gamma delta and T(H)17 cells. Deletion or inhibition of LAT1 efficiently controls IL-23- and IL-1 beta-induced phosphatidylinositol 3-kinase/AKT/mTOR activation independent of T-cell receptor signaling.Conclusion: Targeting LAT1-mediated amino acid uptake is a potentially useful immunosuppressive strategy to control skin inflammation mediated by the IL-23/IL-1 beta/IL-17 axis.