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 Bu

Research output: Contribution to journalArticlepeer-review

85 Scopus citations

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

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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