Opposing roles of the triggering receptor expressed on myeloid cells 2 and triggering receptor expressed on myeloid cells-like transcript 2 in microglia activation

Honghua Zheng, Chia-Chen Liu, Yuka Atagi, Xiao Fen Chen, Lin Jia, Longyu Yang, Wencan He, Xilin Zhang, Sylvia Kang, Terrone L. Rosenberry, John D. Fryer, Yun Wu Zhang, Huaxi Xu, Guojun D Bu

Research output: Contribution to journalArticle

27 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)132-141
Number of pages10
JournalNeurobiology of Aging
Volume42
DOIs
StatePublished - Jun 1 2016

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Microglia
Myeloid Cells
Alzheimer Disease
Lipopolysaccharides
Amyloid
Chromosomes, Human, Pair 6
Brain
Multigene Family
Innate Immunity
Down-Regulation
Cytokines
Gene Expression
Neurons
Mutation

Keywords

  • Inflammation
  • Microglia
  • Proliferation
  • TREM2
  • TREML2

ASJC Scopus subject areas

  • Clinical Neurology
  • Neuroscience(all)
  • Aging
  • Developmental Biology
  • Geriatrics and Gerontology

Cite this

Opposing roles of the triggering receptor expressed on myeloid cells 2 and triggering receptor expressed on myeloid cells-like transcript 2 in microglia activation. / Zheng, Honghua; Liu, Chia-Chen; Atagi, Yuka; Chen, Xiao Fen; Jia, Lin; Yang, Longyu; He, Wencan; Zhang, Xilin; Kang, Sylvia; Rosenberry, Terrone L.; Fryer, John D.; Zhang, Yun Wu; Xu, Huaxi; Bu, Guojun D.

In: Neurobiology of Aging, Vol. 42, 01.06.2016, p. 132-141.

Research output: Contribution to journalArticle

Zheng, Honghua ; Liu, Chia-Chen ; Atagi, Yuka ; Chen, Xiao Fen ; Jia, Lin ; Yang, Longyu ; He, Wencan ; Zhang, Xilin ; Kang, Sylvia ; Rosenberry, Terrone L. ; Fryer, John D. ; Zhang, Yun Wu ; Xu, Huaxi ; Bu, Guojun D. / Opposing roles of the triggering receptor expressed on myeloid cells 2 and triggering receptor expressed on myeloid cells-like transcript 2 in microglia activation. In: Neurobiology of Aging. 2016 ; Vol. 42. pp. 132-141.
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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.",
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T1 - Opposing roles of the triggering receptor expressed on myeloid cells 2 and triggering receptor expressed on myeloid cells-like transcript 2 in microglia activation

AU - Zheng, Honghua

AU - Liu, Chia-Chen

AU - Atagi, Yuka

AU - Chen, Xiao Fen

AU - Jia, Lin

AU - Yang, Longyu

AU - He, Wencan

AU - Zhang, Xilin

AU - Kang, Sylvia

AU - Rosenberry, Terrone L.

AU - Fryer, John D.

AU - Zhang, Yun Wu

AU - Xu, Huaxi

AU - Bu, Guojun D

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AB - 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.

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