Telmisartan prevention of LPS-induced microglia activation involves M2 microglia polarization via CaMKK beta-dependent AMPK activation

doi:10.1016/j.bbi.2015.07.015

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	Telmisartan prevention of LPS-induced microglia activation involves M2 microglia polarization via CaMKK beta-dependent AMPK activation
	Xu, Yuan 2,3; Xu, Yazhou 2,3; Wang, Yurong 2,3; Wang, Yunjie 2,3; He, Ling 2,3; Jiang, Zhenzhou 2,3; Huang, Zhangjian 4; Liao, Hong 2,3; Li, Jia5 ; Saavedra, Juan M.1
刊名	BRAIN BEHAVIOR AND IMMUNITY
	2015-11
卷号	50 页码:298-313
关键词	Telmisartan Microglia polarization AMP-activated protein kinase Neuroinflammation
ISSN号	0889-1591
DOI	10.1016/j.bbi.2015.07.015
文献子类	Article
英文摘要	Brain inflammation plays an important role in the pathophysiology of many psychiatric and neurological diseases. During brain inflammation, microglia cells are activated, producing neurotoxic molecules and neurotrophic factors depending on their pro-inflammatory M1 and anti-inflammatory M2 phenotypes. It has been demonstrated that Angiotensin II type 1 receptor blockers (ARBs) ameliorate brain inflammation and reduce M1 microglia activation. The ARB telmisartan suppresses glutamate-induced upregulation of inflammatory genes in cultured primary neurons. We wished to clarify whether telmisartan, in addition, prevents microglia activation through polarization to an anti-inflammatory M2 phenotype. We found that telmisartan promoted M2 polarization and reduced M1 polarization in LPS-stimulated BV2 and primary microglia cells, effects partially dependent on PPAR gamma activation. The promoting effects of telmisartan on M2 polarization, were attenuated by an AMP-activated protein kinase (AMPK) inhibitor or AMPK knockdown, indicating that AMPK activation participates on telmisartan effects. Moreover, in LPS-stimulated BV2 cells, telmisartan enhancement of M2 gene expression was prevented by the inhibitor STO-609 and siRNA of calmodulin-dependent protein kinase kinase 3 (CaMKK beta), an upstream kinase of AMPK. Furthermore, telmisartan enhanced brain AMPK activation and M2 gene expression in a mouse model of LPS-induced neuroinflammation. In addition, telmisartan reduced the LPS-induced sickness behavior in this in vivo model, and this effect was prevented by prior administration of an AMPK inhibitor. Our results indicate that telmisartan can be considered as a novel AMPK activator, suppressing microglia activation by promoting M2 polarization. Telmisartan may provide a novel, safe therapeutic approach to treat brain disorders associated with enhanced inflammation. (C) 2015 Elsevier Inc. All rights reserved.
资助项目	Natural Science Foundation of Jiangsu Province, China[BK20130653] ; National Natural Science Foundation of China[21402241] ; National Natural Science Foundation of China[81320108029] ; Program for Jiangsu Province "Shuang Chuang" Team[00000000] ; Open Project Program of the State Key Laboratory of Drug Research[SIMM1403KF-02] ; Open Project Program of the State Key Laboratory of Natural Medicines[00000000] ; Fundamental Research Funds for the Central Universities[JKZD2013006] ; Scientific Research Foundation for the Returned Overseas Chinese Scholars, State Education Ministry, China[00000000] ; China Pharmaceutical University[SKLNMKF201407]
WOS关键词	FOCAL CEREBRAL-ISCHEMIA ; PROTEIN-KINASE ; PPAR-GAMMA ; INFLAMMATORY RESPONSE ; HYDROGEN-SULFIDE ; ADIPOSE-TISSUE ; MOUSE MODEL ; DISEASE ; BRAIN ; EXPRESSION
WOS研究方向	Immunology ; Neurosciences & Neurology ; Psychiatry
语种	英语
出版者	ACADEMIC PRESS INC ELSEVIER SCIENCE
WOS记录号	WOS:000364261800032
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/276346]
专题	国家新药筛选中心中科院受体结构与功能重点实验室新药研究国家重点实验室药物安全性评价中心
通讯作者	Zhang, Luyong
作者单位	1.Georgetown Univ, Med Ctr, Dept Pharmacol & Physiol, Washington, DC 20057 USA 2.China Pharmaceut Univ, Jiangsu Key Lab Drug Screening, Nanjing 210009, Jiangsu, Peoples R China; 3.China Pharmaceut Univ, State Key Lab Nat Med, Nanjing 210009, Jiangsu, Peoples R China; 4.China Pharmaceut Univ, Jiangsu Key Lab Drug Discovery Metab Dis, Nanjing 210009, Jiangsu, Peoples R China; 5.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Natl Ctr Drug Screening, Shanghai 201203, Peoples R China;
推荐引用方式 GB/T 7714	Xu, Yuan,Xu, Yazhou,Wang, Yurong,et al. Telmisartan prevention of LPS-induced microglia activation involves M2 microglia polarization via CaMKK beta-dependent AMPK activation[J]. BRAIN BEHAVIOR AND IMMUNITY,2015,50:298-313.
APA	Xu, Yuan.,Xu, Yazhou.,Wang, Yurong.,Wang, Yunjie.,He, Ling.,...&Pang, Tao.(2015).Telmisartan prevention of LPS-induced microglia activation involves M2 microglia polarization via CaMKK beta-dependent AMPK activation.BRAIN BEHAVIOR AND IMMUNITY,50,298-313.
MLA	Xu, Yuan,et al."Telmisartan prevention of LPS-induced microglia activation involves M2 microglia polarization via CaMKK beta-dependent AMPK activation".BRAIN BEHAVIOR AND IMMUNITY 50(2015):298-313.