title: Soluble TREM2 induces inflammatory responses and enhances microglial survival.
abstract: Triggering receptor expressed on myeloid cells 2 (TREM2) is an innate immune receptor expressed in microglia in the brain. A soluble form of TREM2 (sTREM2) derived from proteolytic cleavage of the cell surface receptor is increased in the preclinical stages of AD and positively correlates with the amounts of total and phosphorylated tau in the cerebrospinal fluid. However, the physiological and pathological functions of sTREM2 remain unknown. Here, we show that sTREM2 promotes microglial survival in a PI3K/Akt-dependent manner and stimulates the production of inflammatory cytokines depending on NF-κB. Variants of sTREM2 carrying AD risk-associated mutations were less potent in both suppressing apoptosis and triggering inflammatory responses. Importantly, sTREM2 delivered to the hippocampi of both wild-type andTrem2-knockout mice elevated the expression of inflammatory cytokines and induced morphological changes of microglia. Collectively, these data indicate that sTREM2 triggers microglial activation inducing inflammatory responses and promoting survival. This study has implications for the pathogenesis of AD and provides insights into targeting sTREM2 pathway for AD therapy.
authors.affiliation: Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, Medical College, Xiamen University, Xiamen 361102, China.
authors.forename: Li
authors.initials: L
authors.lastname: Zhong
authors.affiliation: Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, Medical College, Xiamen University, Xiamen 361102, China bu.guojun@mayo.edu chenxf@xmu.edu.cn.|Shenzhen Research Institute of Xiamen University, Shenzhen 518063, China.
authors.forename: Xiao-Fen
authors.identifier: 0000-0002-2435-7982
authors.initials: XF
authors.lastname: Chen
authors.affiliation: Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, Medical College, Xiamen University, Xiamen 361102, China.
authors.forename: Tingting
authors.initials: T
authors.lastname: Wang
authors.affiliation: Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, Medical College, Xiamen University, Xiamen 361102, China.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, Medical College, Xiamen University, Xiamen 361102, China.
authors.forename: Chunyan
authors.initials: C
authors.lastname: Liao
authors.affiliation: Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, Medical College, Xiamen University, Xiamen 361102, China.
authors.forename: Zongqi
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, Medical College, Xiamen University, Xiamen 361102, China.
authors.forename: Ruizhi
authors.initials: R
authors.lastname: Huang
authors.affiliation: Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, Medical College, Xiamen University, Xiamen 361102, China.
authors.forename: Daxin
authors.initials: D
authors.lastname: Wang
authors.affiliation: Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, Medical College, Xiamen University, Xiamen 361102, China.
authors.forename: Xinxiu
authors.initials: X
authors.lastname: Li
authors.affiliation: Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, Medical College, Xiamen University, Xiamen 361102, China.
authors.forename: Linbei
authors.initials: L
authors.lastname: Wu
authors.affiliation: Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, Medical College, Xiamen University, Xiamen 361102, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Jia
authors.affiliation: Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, Medical College, Xiamen University, Xiamen 361102, China.
authors.forename: Honghua
authors.initials: H
authors.lastname: Zheng
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224.
authors.forename: Meghan
authors.identifier: 0000-0002-5950-2449
authors.initials: M
authors.lastname: Painter
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224.
authors.forename: Yuka
authors.identifier: 0000-0002-5194-4269
authors.initials: Y
authors.lastname: Atagi
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224.
authors.forename: Chia-Chen
authors.identifier: 0000-0001-7203-3926
authors.initials: CC
authors.lastname: Liu
authors.affiliation: Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, Medical College, Xiamen University, Xiamen 361102, China.
authors.forename: Yun-Wu
authors.initials: YW
authors.lastname: Zhang
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224.|Neurobiology of Disease Graduate Program, Mayo Clinic, Jacksonville, FL 32224.
authors.forename: John D
authors.initials: JD
authors.lastname: Fryer
authors.affiliation: Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, Medical College, Xiamen University, Xiamen 361102, China.|Neuroscience and Aging Research Center, Sanford-Burnham-Prebys Medical Discovery Institute, La Jolla, CA 92037.
authors.forename: Huaxi
authors.initials: H
authors.lastname: Xu
authors.affiliation: Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, Medical College, Xiamen University, Xiamen 361102, China bu.guojun@mayo.edu chenxf@xmu.edu.cn.|Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224.|Neurobiology of Disease Graduate Program, Mayo Clinic, Jacksonville, FL 32224.
authors.forename: Guojun
authors.initials: G
authors.lastname: Bu
mesh_terms: D000544:Alzheimer Disease / Q000209:etiology; D000818:Animals; D002470:Cell Survival; D000071679:Glycogen Synthase Kinase 3 beta / Q000502:physiology; D057809:HEK293 Cells; D006801:Humans; D007249:Inflammation / Q000209:etiology*; D008562:Membrane Glycoproteins / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000502:physiology*; D009154:Mutation; D016328:NF-kappa B / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D011971:Receptors, Immunologic / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction; D051176:beta Catenin / Q000502:physiology
chemical_list: D008562:Membrane Glycoproteins; D016328:NF-kappa B; D011971:Receptors, Immunologic; C498716:Trem2 protein, mouse; D051176:beta Catenin; D019869:Phosphatidylinositol 3-Kinases; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt