Melatonin, an endogenous hormone, modulates Th17 cells via the reactive-oxygen species/TXNIP/HIF-1α axis to alleviate autoimmune uveitis.
Melatonin, an endogenous hormone, modulates Th17 cells via the reactive-oxygen species/TXNIP/HIF-1α axis to alleviate autoimmune uveitis.
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褪黑激素是一种内源性激素，通过活性氧/TXNIP/HIF-1α 轴调节 Th17 细胞，以缓解自身免疫性葡萄膜炎
DOI：
10.1186/s12974-022-02477-z
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发表时间：
2022-05-27
影响因子：
9.3
通讯作者：
中科院分区：
文献类型：
--
作者：
褪黑激素是松果体分泌的一种吲哚胺，在维持昼夜节律的稳态中起着关键作用。近年来，褪黑素强大的抗氧化和抗炎特性引起了研究者的关注。我们评估了褪黑素在实验性自身免疫性葡萄膜炎（EAU）中的治疗效果，EAU是人类自身免疫性葡萄膜炎的代表性动物模型。通过用肽光感受器间类维生素A结合蛋白1-20（IRBP 1 -20）免疫在小鼠中诱导EAU。然后通过腹膜内注射施用褪黑激素以诱导针对EAU的保护。EAU诱导14天后，对临床和组织病理学评分进行分级，以评估疾病进展。分别通过流式细胞术和RT-PCR检测视网膜中T淋巴细胞的积聚和炎性细胞因子的表达。在体内和体外实验中，通过流式细胞术检测辅助性T细胞1（Th 1）、辅助性T细胞17（Th 17）和调节性T细胞（Treg）。通过流式细胞术检测来自CD 4 + T细胞的活性氧物质（ROS）。免疫印迹法检测硫氧还蛋白相互作用蛋白（TXNIP）和缺氧诱导因子1 α（HIF-1α）的表达。褪黑激素治疗导致EAU小鼠眼部炎症的显著减弱，这通过减少视盘水肿、很少的视网膜血管炎体征以及最小的视网膜和脉络膜浸润来证明。机制研究表明，褪黑素通过抑制Th 1和Th 17细胞的转录因子和增强Treg细胞来限制外周血Th 1和Th 17细胞的增殖。体外研究证实，褪黑激素除了提高Treg细胞的比例外，还抑制视网膜特异性T细胞向Th 17和Th 1细胞的极化。用褪黑激素预处理视网膜特异性T细胞未能诱导幼稚受体的EAU。此外，ROS/ TXNIP/ HIF-1α通路被证明介导褪黑素在EAU中的治疗作用。褪黑激素通过抑制效应T细胞和促进Treg的产生来调节自身免疫T细胞，这表明褪黑激素可能是自身免疫性葡萄膜炎的一种有希望的治疗选择。在线版本包含补充材料，可通过10.1186/s12974-022-02477-z获得。
Melatonin, an indoleamine produced by the pineal gland, plays a pivotal role in maintaining circadian rhythm homeostasis. Recently, the strong antioxidant and anti-inflammatory properties of melatonin have attracted attention of researchers. We evaluated the therapeutic efficacy of melatonin in experimental autoimmune uveitis (EAU), which is a representative animal model of human autoimmune uveitis. EAU was induced in mice via immunization with the peptide interphotoreceptor retinoid binding protein 1–20 (IRBP1–20). Melatonin was then administered via intraperitoneal injection to induce protection against EAU. With EAU induction for 14 days, clinical and histopathological scores were graded to evaluate the disease progression. T lymphocytes accumulation and the expression of inflammatory cytokines in the retinas were assessed via flow cytometry and RT-PCR, respectively. T helper 1 (Th1), T helper 17 (Th17), and regulatory T (Treg) cells were detected via flow cytometry for both in vivo and in vitro experiments. Reactive-oxygen species (ROS) from CD4 + T cells was tested via flow cytometry. The expression of thioredoxin-interacting protein (TXNIP) and hypoxia-inducible factor 1 alpha (HIF-1α) proteins were quantified via western blot. Melatonin treatment resulted in notable attenuation of ocular inflammation in EAU mice, evidenced by decreasing optic disc edema, few signs of retinal vasculitis, and minimal retinal and choroidal infiltrates. Mechanistic studies revealed that melatonin restricted the proliferation of peripheral Th1 and Th17 cells by suppressing their transcription factors and potentiated Treg cells. In vitro studies corroborated that melatonin restrained the polarization of retina-specific T cells towards Th17 and Th1 cells in addition to enhancing the proportion of Treg cells. Pretreatment of retina-specific T cells with melatonin failed to induce EAU in naïve recipients. Furthermore, the ROS/ TXNIP/ HIF-1α pathway was shown to mediate the therapeutic effect of melatonin in EAU. Melatonin regulates autoimmune T cells by restraining effector T cells and facilitating Treg generation, indicating that melatonin could be a hopeful treatment alternative for autoimmune uveitis. The online version contains supplementary material available at 10.1186/s12974-022-02477-z.
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影响因子：
10.3
作者：
Borin TF;Arbab AS;Gelaleti GB;Ferreira LC;Moschetta MG;Jardim-Perassi BV;Iskander AS;Varma NR;Shankar A;Coimbra VB;Fabri VA;de Oliveira JG;Zuccari DA
通讯作者：
Zuccari DA
影响因子：
9.3
作者：
Ali T;Rehman SU;Shah FA;Kim MO
通讯作者：
Kim MO
影响因子：
64.5
作者：
Dang EV;Barbi J;Yang HY;Jinasena D;Yu H;Zheng Y;Bordman Z;Fu J;Kim Y;Yen HR;Luo W;Zeller K;Shimoda L;Topalian SL;Semenza GL;Dang CV;Pardoll DM;Pan F
通讯作者：
Pan F
影响因子：
12.8
作者：
Bing, So Jin;Shemesh, Itay;Caspi, Rachel R.
通讯作者：
Caspi, Rachel R.
影响因子：
64.5
作者：
Farez MF;Mascanfroni ID;Méndez-Huergo SP;Yeste A;Murugaiyan G;Garo LP;Balbuena Aguirre ME;Patel B;Ysrraelit MC;Zhu C;Kuchroo VK;Rabinovich GA;Quintana FJ;Correale J
通讯作者：
Correale J