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The Alzheimer's disease-associated gene TREML2 modulates inflammation by regulating microglia polarization and NLRP3
Si-Yu Wang1, Xin-Xin Fu2, Rui Duan1
1Department of Neurology, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu Province, China.
Abstract:
Triggering receptor expressed on myeloid cells-like 2 (TREML2) is a newly identified susceptibility gene for Alzheimer's disease (AD). It encodes a microglial inflammation-associated receptor. To date, the potential role of microglial TREML2 in neuroinflammation in the context of AD remains unclear. In this study, APP/PS1 mice were used to investigate the dynamic changes of TREML2 levels in brain during AD progression. In addition, lipopolysaccharide (LPS) stimulation of primary microglia as well as a lentivirus-mediated TREML2 overexpression and knockdown were employed to explore the role of TREML2 in neuroinflammation in the context of AD. Our results show that TREML2 levels gradually increased in the brains of APP/PS1 mice during disease progression. LPS stimulation of primary microglia led to the release of inflammatory cytokines including interleukin-1β, interleukin-6, and tumor necrosis factor-α in the culture medium. The LPS-induced microglial release of inflammatory cytokines was enhanced by TREML2 overexpression and was attenuated by TREML2 knockdown. LPS increased the levels of microglial M1-type polarization marker inducible nitric oxide synthase. This effect was enhanced by TREML2 overexpression and ameliorated by TREML2 knockdown. Furthermore, the levels of microglial M2-type polarization markers CD206 and ARG1 in the primary microglia were reduced by TREML2 overexpression and elevated by TREML2 knockdown. LPS stimulation increased the levels of NLRP3 in primary microglia. The LPS-induced increase in NLRP3 was further elevated by TREML2 overexpression and alleviated by TREML2 knockdown. In summary, this study provides the first evidence that TREML2 modulates inflammation by regulating microglial polarization and NLRP3 inflammasome activation. These findings reveal the mechanisms by which TREML2 regulates microglial inflammation and suggest that TREML2 inhibition may represent a novel therapeutic strategy for AD.
Insights
Triggering receptor expressed on myeloid cells-like 2 (TREML2) is linked to Alzheimer's disease (AD). This study shows TREML2 regulates microglial inflammation and NLRP3 inflammasome activation, suggesting TREML2 inhibition as a potential AD therapy.
Area of Science:
- Neuroscience
- Immunology
- Genetics
Background:
- Alzheimer's disease (AD) is a neurodegenerative disorder with a significant inflammatory component.
- Triggering receptor expressed on myeloid cells-like 2 (TREML2) is a newly identified gene associated with AD susceptibility.
- The precise role of TREML2 in microglial-mediated neuroinflammation in AD pathogenesis is not well understood.
Purpose of the Study:
- To investigate the dynamic changes of TREML2 expression in the brain during AD progression.
- To explore the functional role of TREML2 in regulating microglial activation and neuroinflammation in the context of AD.
- To determine if TREML2 influences microglial polarization and NLRP3 inflammasome activation.
Main Methods:
- Utilized APP/PS1 transgenic mice to model AD progression and assess TREML2 levels.
- Employed lipopolysaccharide (LPS) stimulation of primary microglia to induce inflammatory responses.
- Used lentivirus-mediated TREML2 overexpression and knockdown to manipulate TREML2 levels in microglia.
Main Results:
- TREML2 levels progressively increased in the brains of APP/PS1 mice.
- TREML2 overexpression enhanced LPS-induced release of pro-inflammatory cytokines (IL-1β, IL-6, TNF-α) and M1 polarization (iNOS), while suppressing M2 markers (CD206, ARG1).
- TREML2 knockdown attenuated LPS-induced inflammation, M1 polarization, and NLRP3 inflammasome activation.
Conclusions:
- TREML2 plays a significant role in modulating microglial inflammation in the context of AD.
- TREML2 influences neuroinflammation by regulating microglial polarization and activating the NLRP3 inflammasome pathway.
- Targeting TREML2 may offer a novel therapeutic strategy for Alzheimer's disease.
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