TREM2: Potential therapeutic targeting of microglia for Alzheimer's disease

Li, Yueran; Hu, Xu; Wang, Hong; Yang, Kui; Luan, Jiajie; Wang, Sheng

doi:10.1016/j.biopha.2023.115218

Cited by 36 publications

(5 citation statements)

References 159 publications

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“…This buffering is diminished by vancomycin/rest treatment, resulting in hyper-sensitized cell responses upon activation, and the buffering is restored by the administration of L654 ( Figures 5 , 6 ). Finally, these L654-sensitive TLR/NF-κB pathway inhibitors include those such as Trem2 and Irf4 ( 35 – 38 ) that are presently the focus of significant investigation in other cell types and disease-related contexts. This suggests that altering systemic levels of S/G lipids may have translational relevance by altering innate immune inflammatory pathway regulation in contexts such as microglia in CNS disease and T-cell responses in cancer immunotherapy.…”

Section: Discussionmentioning

confidence: 99%

“…Overall, our results suggest that S/G lipids mediate crosstalk between the microbiome and splenic monocytes. By regulating gene expression of inflammatory pathway inhibitors such as Trem2 , S/G lipids merit broader investigation into the potential dysfunction of other innate immune cells, such as microglia, in diseases such as Alzheimer’s disease ( 37 , 38 ).…”

Section: Discussionmentioning

confidence: 99%

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Microbiome-derived bacterial lipids regulate gene expression of proinflammatory pathway inhibitors in systemic monocytes

Mihori,

Nichols,

Provatas

et al. 2024

Front. Immunol.

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How the microbiome regulates responses of systemic innate immune cells is unclear. In the present study, our purpose was to document a novel mechanism by which the microbiome mediates crosstalk with the systemic innate immune system. We have identified a family of microbiome Bacteroidota-derived lipopeptides—the serine-glycine (S/G) lipids, which are TLR2 ligands, access the systemic circulation, and regulate proinflammatory responses of splenic monocytes. To document the role of these lipids in regulating systemic immunity, we used oral gavage with an antibiotic to decrease the production of these lipids and administered exogenously purified lipids to increase the systemic level of these lipids. We found that decreasing systemic S/G lipids by decreasing microbiome Bacteroidota significantly enhanced splenic monocyte proinflammatory responses. Replenishing systemic levels of S/G lipids via exogenous administration returned splenic monocyte responses to control levels. Transcriptomic analysis demonstrated that S/G lipids regulate monocyte proinflammatory responses at the level of gene expression of a small set of upstream inhibitors of TLR and NF-κB pathways that include Trem2 and Irf4. Consistent with enhancement in proinflammatory cytokine responses, decreasing S/G lipids lowered gene expression of specific pathway inhibitors. Replenishing S/G lipids normalized gene expression of these inhibitors. In conclusion, our results suggest that microbiome-derived S/G lipids normally establish a level of buffered signaling activation necessary for well-regulated innate immune responses in systemic monocytes. By regulating gene expression of inflammatory pathway inhibitors such as Trem2, S/G lipids merit broader investigation into the potential dysfunction of other innate immune cells, such as microglia, in diseases such as Alzheimer’s disease.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Microbiome-derived bacterial lipids regulate gene expression of proinflammatory pathway inhibitors in systemic monocytes

Mihori,

Nichols,

Provatas

et al. 2024

Front. Immunol.

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“…These reactions have attracted much attention due to their ability to produce complex polycyclic structures ( e.g. natural products, pharmaceuticals, or valuable intermediates) 11–55 (Scheme 1).…”

Section: From Classical Cycloadditions To Higher-order Cycloadditionsmentioning

confidence: 99%

Recent advances in metal-free catalytic enantioselective higher-order cycloadditions

Zhang,

Wang

2024

Org. Chem. Front.

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“…NHC-catalyzed transformation has proven to be a powerful class of synthetic tools that can be used to assemble numerous biologically important or medicinal skeletons. − Among NHC-bounded intermediates, α,β-unsaturated acyl azoliums are classified as electrophilic cationic species − due to their LOMO activation. , As shown in Figure a, a number of nucleophiles have been reported to react with α,β-unsaturated acyl azoliums to achieve diversified β-functionalizations. Within this context, the α-Csp 3 contained carbonyls − or imines ,− and benzylic-type ,, nucleophiles were widely explored.…”

Section: Introductionmentioning

confidence: 99%

Carbene-Catalyzed Enantioselective Petasis-Like Alkenylation

Li,

Zhang,

et al. 2024

ACS Catal.

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The N-heterocyclic carbene (NHC)-catalyzed enantioselective Petasis-like alkenylation of o-hydroxycinnamaldehydes or hydroxyl-tethered α,β-unsaturated aldehydes with styryl, dienyl, or trienyl boronic acids is disclosed. This method involves the addition of π-system-containing boronic acids to NHC-bounded α,β-unsaturated acyl azoliums and allows access to divergent assembly of β-alkenyl substituted dihydrocoumarin and γand δ-lactones. DFT calculations suggest that an unprecedented zwitterionic intermediate and 1,4-or 1,5-migration of alkenyl groups play a crucial role in the reaction. More in-depth studies of orbital and noncovalent interaction analysis provide more detailed explanations for pathways and stereoselectivity control.

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TREM2: Potential therapeutic targeting of microglia for Alzheimer's disease

Cited by 36 publications

References 159 publications

Microbiome-derived bacterial lipids regulate gene expression of proinflammatory pathway inhibitors in systemic monocytes

Microbiome-derived bacterial lipids regulate gene expression of proinflammatory pathway inhibitors in systemic monocytes

Recent advances in metal-free catalytic enantioselective higher-order cycloadditions

Carbene-Catalyzed Enantioselective Petasis-Like Alkenylation

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