College of Pharmacy, Yeungnam University, 280 Daehak-Ro, Gyeongsan, Gyeongbuk, 38541, Republic of Korea.
Department of Pharmacology, School of Medicine, Catholic University of Daegu, 33 Duryugongwon-ro 17-gil, Nam-gu, Daegu, Republic of Korea.
Sci Rep. 2017 Jul 25;7(1):6444. doi: 10.1038/s41598-017-06835-3.
Sirt1, a key regulator of metabolism and longevity, has recently been implicated in the regulation of allergic reactions, although the underlying mechanism remains unclear. Here we show that Sirt1 negatively regulates FcεRI-stimulated mast cell activation and anaphylaxis through two mutually regulated pathways involving AMP-activated protein kinase (AMPK) and protein tyrosine phosphatase 1B (PTP1B). Mast cell-specific knockout of Sirt1 dampened AMPK-dependent suppression of FcεRI signaling, thereby augmenting mast cell activation both in vitro and in vivo. Sirt1 inhibition of FcεRI signaling also involved an alternative component, PTP1B, which attenuated the inhibitory AMPK pathway and conversely enhanced the stimulatory Syk pathway, uncovering a novel role of this phosphatase. Moreover, a Sirt1 activator resveratrol stimulated the inhibitory AMPK axis, with reciprocal suppression of the stimulatory PTP1B/Syk axis, thus potently inhibiting anaphylaxis. Overall, our results provide a molecular explanation for the beneficial role of Sirt1 in allergy and underscore a potential application of Sirt1 activators as a new class of anti-allergic agents.
Sirt1 是代谢和长寿的关键调节因子，最近被牵连到过敏反应的调节中，尽管其潜在机制尚不清楚。在这里，我们表明 Sirt1 通过两条相互调节的途径负调节 FcεRI 刺激的肥大细胞活化和过敏反应，涉及 AMP 激活的蛋白激酶 (AMPK) 和蛋白酪氨酸磷酸酶 1B (PTP1B)。肥大细胞特异性敲除 Sirt1 减弱了 AMPK 依赖性 FcεRI 信号的抑制，从而增强了体外和体内的肥大细胞活化。Sirt1 对 FcεRI 信号的抑制还涉及另一个组成部分 PTP1B，它减弱了抑制 AMPK 途径，相反增强了刺激 Syk 途径，揭示了这种磷酸酶的新作用。此外，Sirt1 激活剂白藜芦醇刺激抑制性 AMPK 轴，同时抑制刺激性 PTP1B/Syk 轴，从而有效地抑制过敏反应。总的来说，我们的结果为 Sirt1 在过敏中的有益作用提供了分子解释，并强调了 Sirt1 激活剂作为一类新的抗过敏药物的潜在应用。
