CB2 receptor activation inhibits the phagocytic function of microglia through activating ERK/AKT-Nurr1 signal pathways  

作　　者：Qi-wen Han Qian-hang Shao Xiao-tong Wang Kai-li Ma Nai-hong Chen Yu-he Yuan 

机构地区：[1]State Key Laboratory of Bioactive Substances and Functions of Natural Medicines,Institute of Materia Medica&Neuroscience Center,Chinese Academy of Medical Sciences and Peking Union Medical College,Beijing 100050,China [2]Institute of Medical Biology,Chinese Academy of Medical Sciences and Peking Union Medical College,Kunming 650118,China

出　　处：《Acta Pharmacologica Sinica》2022年第9期2253-2266,共14页中国药理学报（英文版）

基　　金：This work was supported by National Health Commission Key Laboratory of Drug Addiction Medicine,the First Affiliated Hospital of Kunming Medical University(Kunming,China,2020DAMOP-008);the National Natural Science Foundation of China(81773925 and 82104418);the Beijing Natural Science Foundation(7212156),CAMS Innovation Fund for Medical Sciences(2021-I2M-1-026);the Fundamental Research Funds for the Central Universities(3332019154 and 3332019153).

摘　　要：Neuroinflammation is closely related to the pathogenesis of neurodegenerative diseases.Activation of microglia,the resident immune cells in CNS,induces inflammatory responses,resulting in the release of neurotoxic molecules,which favors neuronal death and neurodegeneration.Nuclear receptor-related 1(Nurr1)protein,one of the orphan nuclear receptor superfamilies,is an emerging target for neuroprotective therapy.In addition,the anti-inflammatory function of cannabinoid(CB)receptors has attracted increasing interest.As both CB receptors(especially CB2 receptor)and Nurr1 exist in microglia,and regulate a number of same molecular points such as NF-κB,we herein explored the interplay between the CB2 receptor and Nurr1 as well as the regulatory mechanisms in microglial cells.We showed that the application of CB2 receptor agonists JWH015(1,10μM)significantly increased the nuclear Nurr1 protein in BV-2 cells and primary midbrain microglia.Overexpression of Nurr1 or application of Nurr1 agonist C-DIM12(10μM)significantly increased the mRNA level of CB2 receptor in BV-2 cells,suggesting that positive expression feedback existing between the CB2 receptor and Nurr1.After 2-AG and JWH015 activated the CB2 receptors,the levels of p-ERK,p-AKT,p-GSK-3βin BV-2 cells were significantly increased.Using ERK1/2 inhibitor U0126 and PI3K/AKT inhibitor LY294002,we revealed that the amount of Nurr1 in the nucleus was upregulated throughβ-arrestin2/ERK1/2 and PI3K/AKT/GSK-3βsignaling pathways.With these inhibitors,we found a cross-talk interaction between the two pathways,and the ERK1/2 signaling pathway played a more dominant regulatory role.Furthermore,we demonstrated that when the CB2 receptor was activated,the phagocytic function of BV-2 cells was significantly weakened;the activation of Nurr1 also inhibited the phagocytic function of BV-2 cells.Pretreatment with the signaling pathway inhibitors,especially U0126,reversed the inhibitory effect of 2-AG on phagocytosis,suggesting that CB2 receptor may regulate the phagocytic functio

关 键 词：NEUROINFLAMMATION MICROGLIA cannabinoid receptor 2 NURR1 PHAGOCYTOSIS 

分 类 号：R965[医药卫生—药理学]