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-KB,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(10 μM)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-3β in 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 through β-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 function of microglia by activating Nurr1.In conclusion,CB2 receptor or/and Nurr1-mediated signal pathways play instrumental roles in the progress of phagocytosis,which are expected to open up new treatment strategies for neurodegenerative diseases.

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

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;Institute of Medical Biology,Chinese Academy of Medical Sciences and Peking Union Medical College,Kunming 650118,China

中国药理学报（英文版）

[1]Qi-wen Han;Qian-hang Shao;Xiao-tong Wang;Kai-li Ma;Nai-hong Chen;Yu-he Yuan-.CB2 receptor activation inhibits the phagocytic function of microglia through activating ERK/AKT-Nurrl signal pathways)[J].中国药理学报（英文版）,2022(09):2253-2266

Nurrl,superfamilies,JWH015,DIM12

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