Soluble TREM2 induces inflammatory responses and enhances microglial survival

Li Zhong, Xiao Fen Chen, Tingting Wang, Zhe Wang, Chunyan Liao, Zongqi Wang, Ruizhi Huang, Daxin Wang, Xinxiu Li, Linbei Wu, Lin Jia, Honghua Zheng, Meghan Painter, Yuka Atagi, Chia-Chen Liu, Yun Wu Zhang, John D. Fryer, Huaxi Xu, Guojun D Bu

Research output: Contribution to journalArticle

51 Citations (Scopus)

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 and Trem2-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.

Original languageEnglish (US)
Pages (from-to)597-607
Number of pages11
JournalThe Journal of experimental medicine
Volume214
Issue number3
DOIs
StatePublished - Mar 6 2017
Externally publishedYes

Fingerprint

Microglia
Myeloid Cells
Cytokines
Cell Surface Receptors
Phosphatidylinositol 3-Kinases
Knockout Mice
Cerebrospinal Fluid
Hippocampus
Mutation
Brain
Therapeutics
Pyroptosis

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Soluble TREM2 induces inflammatory responses and enhances microglial survival. / Zhong, Li; Chen, Xiao Fen; Wang, Tingting; Wang, Zhe; Liao, Chunyan; Wang, Zongqi; Huang, Ruizhi; Wang, Daxin; Li, Xinxiu; Wu, Linbei; Jia, Lin; Zheng, Honghua; Painter, Meghan; Atagi, Yuka; Liu, Chia-Chen; Zhang, Yun Wu; Fryer, John D.; Xu, Huaxi; Bu, Guojun D.

In: The Journal of experimental medicine, Vol. 214, No. 3, 06.03.2017, p. 597-607.

Research output: Contribution to journalArticle

Zhong, L, Chen, XF, Wang, T, Wang, Z, Liao, C, Wang, Z, Huang, R, Wang, D, Li, X, Wu, L, Jia, L, Zheng, H, Painter, M, Atagi, Y, Liu, C-C, Zhang, YW, Fryer, JD, Xu, H & Bu, GD 2017, 'Soluble TREM2 induces inflammatory responses and enhances microglial survival', The Journal of experimental medicine, vol. 214, no. 3, pp. 597-607. https://doi.org/10.1084/jem.20160844
Zhong, Li ; Chen, Xiao Fen ; Wang, Tingting ; Wang, Zhe ; Liao, Chunyan ; Wang, Zongqi ; Huang, Ruizhi ; Wang, Daxin ; Li, Xinxiu ; Wu, Linbei ; Jia, Lin ; Zheng, Honghua ; Painter, Meghan ; Atagi, Yuka ; Liu, Chia-Chen ; Zhang, Yun Wu ; Fryer, John D. ; Xu, Huaxi ; Bu, Guojun D. / Soluble TREM2 induces inflammatory responses and enhances microglial survival. In: The Journal of experimental medicine. 2017 ; Vol. 214, No. 3. pp. 597-607.
@article{9846ceeb66e046d2aae3d1c423f1d49b,
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 and Trem2-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.",
author = "Li Zhong and Chen, {Xiao Fen} and Tingting Wang and Zhe Wang and Chunyan Liao and Zongqi Wang and Ruizhi Huang and Daxin Wang and Xinxiu Li and Linbei Wu and Lin Jia and Honghua Zheng and Meghan Painter and Yuka Atagi and Chia-Chen Liu and Zhang, {Yun Wu} and Fryer, {John D.} and Huaxi Xu and Bu, {Guojun D}",
year = "2017",
month = "3",
day = "6",
doi = "10.1084/jem.20160844",
language = "English (US)",
volume = "214",
pages = "597--607",
journal = "Journal of Experimental Medicine",
issn = "0022-1007",
publisher = "Rockefeller University Press",
number = "3",

}

TY - JOUR

T1 - Soluble TREM2 induces inflammatory responses and enhances microglial survival

AU - Zhong, Li

AU - Chen, Xiao Fen

AU - Wang, Tingting

AU - Wang, Zhe

AU - Liao, Chunyan

AU - Wang, Zongqi

AU - Huang, Ruizhi

AU - Wang, Daxin

AU - Li, Xinxiu

AU - Wu, Linbei

AU - Jia, Lin

AU - Zheng, Honghua

AU - Painter, Meghan

AU - Atagi, Yuka

AU - Liu, Chia-Chen

AU - Zhang, Yun Wu

AU - Fryer, John D.

AU - Xu, Huaxi

AU - Bu, Guojun D

PY - 2017/3/6

Y1 - 2017/3/6

N2 - 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 and Trem2-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.

AB - 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 and Trem2-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.

UR - http://www.scopus.com/inward/record.url?scp=85020604923&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85020604923&partnerID=8YFLogxK

U2 - 10.1084/jem.20160844

DO - 10.1084/jem.20160844

M3 - Article

C2 - 28209725

AN - SCOPUS:85020604923

VL - 214

SP - 597

EP - 607

JO - Journal of Experimental Medicine

JF - Journal of Experimental Medicine

SN - 0022-1007

IS - 3

ER -