title: Opposing roles of the triggering receptor expressed on myeloid cells 2 and triggering receptor expressed on myeloid cells-like transcript 2 in microglia activation.
abstract: Mutations in triggering receptor expressed on myeloid cells 2 (TREM2), which has been proposed to regulate the inflammatory responses and the clearance of apoptotic neurons and/or amyloid-β, are genetically linked to increased risk for late-onset Alzheimer's disease (AD). Interestingly, a missense variant in TREM-like transcript 2 (TREML2), a structurally similar protein encoded by the same gene cluster with TREM2 on chromosome 6, has been shown to protect against AD. However, the molecular mechanisms by which TREM2 and TREML2 regulate the pathogenesis of AD, and their functional relationship, if any, remain unclear. Here, we show that lipopolysaccharide (LPS) stimulation significantly suppressed TREM2 but increased TREML2 expression in mouse brain. Consistent with this in vivo result, LPS or oligomeric amyloid-β treatment down regulated TREM2 but up-regulated TREML2 expression in primary microglia. Most important, modulation of TREM2 or TREML2 levels had opposing effects on inflammatory responses with enhancement or suppression of LPS-induced proinflammatory cytokine gene expression observed on TREM2 or TREML2 down regulation, respectively. In addition, the proliferation of primary microglia was significantly decreased when TREM2 was down regulated, whereas it was increased on TREML2 knockdown. Together, our results suggest that several microglial functions are strictly regulated by TREM2 and TREML2, whose dysfunctions likely contribute to AD pathogenesis by impairing brain innate immunity. Our findings provide novel mechanistic insights into the functions of TREM2 and TREML2 in microglia and have implications on designing new therapeutic strategies to treat AD.
authors.affiliation: Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, Medical College, Xiamen University, Xiamen, PR China.
authors.forename: Honghua
authors.initials: H
authors.lastname: Zheng
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
authors.forename: Chia-Chen
authors.initials: CC
authors.lastname: Liu
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Atagi
authors.affiliation: Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, Medical College, Xiamen University, Xiamen, PR China.
authors.forename: Xiao-Fen
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, PR 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, PR China.
authors.forename: Longyu
authors.initials: L
authors.lastname: Yang
authors.affiliation: Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, Medical College, Xiamen University, Xiamen, PR China.
authors.forename: Wencan
authors.initials: W
authors.lastname: He
authors.affiliation: Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, Medical College, Xiamen University, Xiamen, PR China.
authors.forename: Xilin
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
authors.forename: Silvia S
authors.initials: SS
authors.lastname: Kang
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
authors.forename: Terrone L
authors.initials: TL
authors.lastname: Rosenberry
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA; Neurobiology of Disease Graduate Program, Mayo Clinic, Jacksonville, FL, USA.
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, PR China; Degenerative Disease Research Program, Sanford-Burnham Medical Research Institute, La Jolla, CA, USA.
authors.forename: Yun-Wu
authors.initials: YW
authors.lastname: Zhang
authors.affiliation: Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, Medical College, Xiamen University, Xiamen, PR China; Degenerative Disease Research Program, Sanford-Burnham Medical Research Institute, La Jolla, CA, USA.
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, PR China; Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA; Neurobiology of Disease Graduate Program, Mayo Clinic, Jacksonville, FL, USA. Electronic address: bu.guojun@mayo.edu.
authors.forename: Guojun
authors.initials: G
authors.lastname: Bu
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001921:Brain / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation; D015870:Gene Expression; D007113:Immunity, Innate; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000502:physiology*; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000378:metabolism / Q000473:pathology / Q000502:physiology*; D058990:Molecular Targeted Therapy; D009154:Mutation; D011971:Receptors, Immunologic / Q000235:genetics* / Q000502:physiology*; D015854:Up-Regulation
chemical_list: D016229:Amyloid beta-Peptides; D016207:Cytokines; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D011971:Receptors, Immunologic; C473367:TREML2 protein, human; C498716:Trem2 protein, mouse
keywords: Inflammation; Microglia; Proliferation; TREM2; TREML2