Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UNIPROT:P43026 (lipopolysaccharide)
62,215 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Triggering receptor expressed on myeloid cells 2 (Trem2), an immune-modulatory receptor, is preferentially expressed in microglia of central nervous system. Trem2 might be involved in the development of Alzheimer's disease (AD) through regulating the inflammatory responses and phagocytosis of microglia. However, the intracellular trafficking of Trem2 remains unclear. In this study, we showed that Trem2 in the plasma membrane underwent endocytosis and recycling. Trem2 is internalized in a clathrin-dependent manner and then recycled back to the plasma membrane through vacuolar protein sorting 35 (Vps35), the key component of cargo recognition core of retromer complex, but not Rab11. When Vps35 is knocked down, Trem2 accumulated in the lysosomes but was not degraded. More importantly, Vps35 deficiency leads to excessive lipopolysaccharide (LPS)-induced inducible nitric oxide synthase (iNOS) expression and IL-6 production, which can be abolished by Trem2 overexpression. Furthermore, R47H Trem2, an AD-associated mutant, failed to interact with Vps35 and became unstable compared with wild-type Trem2. Our study suggests that Vps35/retromer is responsible for recycling of Trem2 in the regulation of microglial function such as proinflammatory responses, whereas R47H mutation impairs Trem2 trafficking, which might contribute to AD.
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PMID:Vps35-dependent recycling of Trem2 regulates microglial function. 2771 39

Microglia play an important role in mediating inflammatory processes in the central nervous system (CNS). Triggering receptor expressed on myeloid cells 2 (TREM2) is a microglia-specific receptor and could decrease neuropathology in Alzheimer's disease (AD). However, the detailed mechanism remains unclear. This study was designed to elucidate the effect of TREM2 on microglia. We showed that lipopolysaccharide (LPS) stimulation significantly increases proinflammatory cytokines and suppressed TREM2 in microglia. In addition, TREM2 overexpression inhibited LPS-induced microglia activation and elevated M2 phenotype of microglia. Together, our results demonstrate that TREM2 overexpression reduced LPS-induced proinflammatory cytokine release in microglia and increased M2 phenotype of microglia. These findings provide novel insights that the regulation of microglia polarization may be an approach for ameliorating microglia inflammation in neurodegenerative diseases.
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PMID:Triggering Receptor Expressed on Myeloid Cells 2 Overexpression Inhibits Proinflammatory Cytokines in Lipopolysaccharide-Stimulated Microglia. 2918 Aug 39

Triggering receptor expressed on myeloid cells 2 (TREM2) is an orphan immune receptor expressed on cells of myeloid lineage such as macrophages and microglia. The rare variant R47H TREM2 is associated with an increased risk for Alzheimer's disease, supporting the hypothesis that TREM2 loss of function may exacerbate disease progression. However, a complete knockout of the TREM2 gene in different genetic models of neurodegenerative diseases has been reported to result in both protective and deleterious effects on disease-related end points and myeloid cell function. Here, we describe a Trem2^R47H transgenic mouse model and report that even in the absence of additional genetic perturbations, this variant clearly confers a loss of function on myeloid cells. The Trem2^R47H variant-containing myeloid cells exhibited subtle defects in survival and migration and displayed an unexpected dysregulation of cytokine responses in a lipopolysaccharide challenge environment. These subtle phenotypic defects with a gradation in severity across genotypes were confirmed in whole-genome RNA-Seq analyses of WT, Trem2^-/-, and Trem2^R47H myeloid cells under challenge conditions. Of note, TREM2-activating antibodies that boost proximal signaling abrogated survival defects conferred by the variant and also modulated migration and cytokine responses in an antibody-, ligand-, and challenge-dependent manner. In some instances, these antibodies also boosted WT myeloid cell function. Our studies provide a first glimpse into the boost in myeloid cell function that can be achieved by pharmacological modulation of TREM2 activity that can potentially be ameliorative in neurodegenerative diseases such as Alzheimer's disease.
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PMID:TREM2-activating antibodies abrogate the negative pleiotropic effects of the Alzheimer's disease variant Trem2^R47H on murine myeloid cell function. 2959 91

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