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Opposing roles of the triggering receptor expressed on myeloid cells 2 and triggering receptor expressed on myeloid
Honghua Zheng1, Chia-Chen Liu2, Yuka Atagi2
1Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, Medical College, Xiamen University, Xiamen, PR China.
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.
Insights
Triggering receptor expressed on myeloid cells 2 (TREM2) and TREM-like transcript 2 (TREML2) impact Alzheimer's disease (AD) by regulating microglial functions. Their opposing roles in inflammation and proliferation offer new therapeutic targets for AD.
Area of Science:
- Neuroscience
- Immunology
- Genetics
Background:
- Mutations in TREM2 (triggering receptor expressed on myeloid cells 2) increase late-onset Alzheimer's disease (AD) risk.
- TREML2 (TREM-like transcript 2), a related gene, has a variant protective against AD.
- The functional relationship and molecular mechanisms of TREM2 and TREML2 in AD pathogenesis are unclear.
Purpose of the Study:
- To elucidate the distinct roles of TREM2 and TREML2 in microglial function.
- To investigate the impact of TREM2 and TREML2 modulation on inflammatory responses and microglial proliferation.
- To explore the implications for Alzheimer's disease pathogenesis and therapeutic strategies.
Main Methods:
- In vivo studies using lipopolysaccharide (LPS) stimulation in mouse brain.
- In vitro experiments with primary microglia treated with LPS or oligomeric amyloid-β.
- Analysis of TREM2 and TREML2 expression levels.
- Assessment of inflammatory cytokine gene expression and microglial proliferation.
Main Results:
- LPS stimulation suppressed TREM2 but increased TREML2 expression in vivo and in primary microglia.
- Amyloid-β treatment similarly altered TREM2 and TREML2 expression in microglia.
- Down-regulation of TREM2 enhanced inflammatory responses and decreased proliferation.
- Down-regulation of TREML2 suppressed inflammatory responses and increased proliferation.
Conclusions:
- TREM2 and TREML2 exhibit opposing regulatory effects on microglial inflammatory responses and proliferation.
- Dysregulation of TREM2 and TREML2 function likely contributes to AD pathogenesis by impairing brain innate immunity.
- These findings offer novel mechanistic insights into TREM2 and TREML2 functions and suggest potential therapeutic avenues for AD.
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