Activation of N-methyl-D-aspartate receptor downregulates inflammasome activity and liver inflammation via a β-arrestin-2 pathway
Activation of N-methyl-D-aspartate receptor downregulates inflammasome activity and liver inflammation via a β-arrestin-2 pathway
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DOI：
10.1152/ajpgi.00073.2014
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发表时间：
2014-10-01
影响因子：
4.5
通讯作者：
Mehal, Wajahat Zafar
中科院分区：
文献类型：
--
作者：
Farooq, Ahmad;Hoque, Rafaz;Mehal, Wajahat Zafar
细胞溶质炎性体机制的激活是急性和慢性肝脏炎症的原因，但对其调控知之甚少。N-甲基-D天冬氨酸（NMDA）受体家族是异四聚体配体门控离子通道，可被一系列代谢物激活，包括天冬氨酸、谷氨酸和多不饱和脂肪酸。在脑中，NMDA受体存在于神经元和非神经元细胞上，并调节多种功能。我们测试了NMDA受体和天冬氨酸在体外炎性小体调节和急性肝炎和胰腺炎模型中的作用。我们证明了NMDA受体存在于Kupffer细胞上，并且它们在原代小鼠和人细胞上的激活通过下调NOD样受体家族、含有pyrin结构域3和procaspase-1来限制炎性小体激活。NMDA受体途径在体内是活性的，限制急性肝炎中的损伤，并且可以通过天冬氨酸在治疗上进一步激活，从而在急性炎性肝损伤中提供保护。NMDA对炎性小体活化的下调通过β-抑制蛋白-2 NF-κ β和JNK途径而不是通过Ca 2+动员发生。我们已经确定了NMDA受体在体外和体内的炎症活动的调节。这已经确定了与代谢物相关的免疫调节的新领域，这些代谢物可能与各种疾病相关，包括非酒精性脂肪性肝炎和全胃肠外营养诱导的免疫抑制。
Activation of the cytosolic inflammasome machinery is responsible for acute and chronic liver inflammation, but little is known about its regulation. The N-methyl-Daspartate (NMDA) receptor families are heterotetrameric ligand-gated ion channels that are activated by a range of metabolites, including aspartate, glutamate, and polyunsaturated fatty acids. In the brain NMDA receptors are present on neuronal and nonneuronal cells and regulate a diverse range of functions. We tested the role of the NMDA receptor and aspartate in inflammasome regulation in vitro and in models of acute hepatitis and pancreatitis. We demonstrate that the NMDA receptor is present on Kupffer cells, and their activation on primary mouse and human cells limits inflammasome activation by downregulating NOD-like receptor family, pyrin domain containing 3 and procaspase-1. The NMDA receptor pathway is active in vivo, limits injury in acute hepatitis, and can be therapeutically further activated by aspartate providing protection in acute inflammatory liver injury. Downregulation of inflammasome activation by NMDA occurs via a beta-arrestin-2 NF-k beta and JNK pathway and not via Ca2+ mobilization. We have identified the NMDA receptor as a regulator of inflammasome activity in vitro and in vivo. This has identified a new area of immune regulation associated by metabolites that may be relevant in a diverse range of conditions, including nonalcoholic steatohepatitis and total parenteral nutrition-induced immune suppression.