Article

Cutting Edge: TREM-2 Attenuates Macrophage Activation

Department of Pathology and Immunology, Washington University in St. Louis, San Luis, Missouri, United States
The Journal of Immunology (Impact Factor: 4.92). 10/2006; 177(6):3520-4. DOI: 10.4049/jimmunol.177.6.3520
Source: PubMed

ABSTRACT

The triggering receptor expressed on myeloid cells 2 (TREM-2) delivers intracellular signals through the adaptor DAP12 to regulate myeloid cell function both within and outside the immune system. The role of TREM-2 in immunity has been obscured by the failure to detect expression of the TREM-2 protein in vivo. In this study, we show that TREM-2 is expressed on macrophages infiltrating the tissues from the circulation and that alternative activation with IL-4 can induce TREM-2. TREM-2 expression is abrogated by macrophage maturation with LPS of IFN-gamma. Using TREM-2(-/-) mice, we find that TREM-2 functions to inhibit cytokine production by macrophages in response to the TLR ligands LPS, zymosan, and CpG. Furthermore, we find that TREM-2 completely accounts for the increased cytokine production previously reported by DAP12(-/-) macrophages. Taken together, these data show that TREM-2 is expressed on newly differentiated and alternatively activated macrophages and functions to restrain macrophage activation.

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    • "The physiological functions of TREM2 are not fully understood. On the one hand, macrophages of TREM2 knockout (KO) mice show increased production of inflammatory cytokines upon Toll-like receptor activa- tion[20]and decreased phagocytic activity[15]. On the other hand, activation of TREM2 in microglia increased the expression of chemokine receptors and cell migra- tion[21,22]. "
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    ABSTRACT: Background: Triggering receptor expressed on myeloid cells-2 (TREM2) exerts important functions in the regulation of monocytes, like dendritic cells, osteoclasts, tissue macrophages, and microglia. Mutations in TREM2 are associated with several diseases, including Nasu-Hakola disease, frontotemporal dementia, and Alzheimer's disease (AD). TREM2 undergoes sequential proteolytic processing by ectodomain shedding and intramembrane proteolysis. Findings: We show that inhibition of γ-secretase-dependent cleavage of the TREM2 C-terminal fragment in cellular membranes interferes with TREM2-dependent signaling and cellular function. Inhibition of γ-secretase decreases membrane-proximal signaling and intracellular Ca2+ response. Decreased signaling alters morphological changes and phagocytic activity of cells upon selective stimulation of TREM2. Conclusions: The data demonstrate the importance of γ-secretase-dependent intramembrane processing in TREM2-mediated signaling and, thus, a functional relation of two AD-associated proteins.
    Preview · Article · Dec 2016 · Journal of Neuroinflammation
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    • "Recently an increased risk of AD was found to be related to heterozygous variants in the triggering receptor expressed on myeloid cells 2 protein (TREM2) [33]. TREM2 is expressed on alternatively activated M2 macrophages and attenuates macrophage activation [34]. GPCRs are the most interesting from the omega- 3 therapeutic viewpoint as the ALX/FPR2 antagonist blocked A 1-42 -induced IL-1 in monocytes [35] and ALX/FPR2 antibody blocked enhancement of A 1-42 phagocytosis by resolvin D1 [36]. "
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    ABSTRACT: In this review we discuss the immunopathology of Alzheimer's disease (AD) and recent advances in the prevention of minor cognitive impairment (MCI) by nutritional supplementation with omega-3 fatty acids. Defective phagocytosis of amyloid-β (Aβ) and abnormal inflammatory activation of peripheral blood mononuclear cells (PBMCs) are the two key immune pathologies of MCI and AD patients. The phagocytosis of Aβ by PBMCs of MCI and AD patients is universally defective and the inflammatory gene transcription is heterogeneously deregulated in comparison to normal subjects. Recent studies have discovered a cornucopia of beneficial anti-inflammatory and pro-resolving effects of the specialized proresolving mediators (SPMs) resolvins, protectins, maresins, and their metabolic precursors. Resolvin D1 and other mediators switch macrophages from an inflammatory to a tissue protective/pro-resolving phenotype and increase phagocytosis of Aβ. In a recent study of AD and MCI patients, nutritional supplementation by omega-3 fatty acids individually increased resolvin D1, improved Aβ phagocytosis, and regulated inflammatory genes toward a physiological state, but only in MCI patients. Our studies are beginning to dissect positive factors (adherence to Mediterranean diet with omega-3 and exercise) and negative factors (high fat diet, infections, cancer, and surgeries) in each patient. The in vitro and in vivo effects of omega-3 fatty acids and SPMs suggest that defective phagocytosis and chronic inflammation are related to defective production and/or defective signaling by SPMs in immune cells.
    Full-text · Article · Sep 2015 · Journal of Alzheimer's disease: JAD
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    • "4 Cell 160, 1–11, March 12, 2015 ª2015 Elsevier Inc. Please cite this article in press as: Wang et al., TREM2 Lipid Sensing Sustains the Microglial Response in an Alzheimer's Disease Model, Cell (2015), http://dx.doi.org/10.1016/j.cell.2015.01.049 (Hamerman et al., 2006; Turnbull et al., 2006). Moreover, TREM2 deficiency had very little impact on microglial uptake of Ab aggregates (Figure S5E; Movie S4) or their subsequent proteolytic processing, as demonstrated by similar degradation of the intracellular concentration of Ab after initial loading (Figure S5F). "
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    ABSTRACT: Triggering receptor expressed on myeloid cells 2 (TREM2) is a microglial surface receptor that triggers intracellular protein tyrosine phosphorylation. Recent genome-wide association studies have shown that a rare R47H mutation of TREM2 correlates with a substantial increase in the risk of developing Alzheimer's disease (AD). To address the basis for this genetic association, we studied TREM2 deficiency in the 5XFAD mouse model of AD. We found that TREM2 deficiency and haploinsufficiency augment β-amyloid (Aβ) accumulation due to a dysfunctional response of microglia, which fail to cluster around Aβ plaques and become apoptotic. We further demonstrate that TREM2 senses a broad array of anionic and zwitterionic lipids known to associate with fibrillar Aβ in lipid membranes and to be exposed on the surface of damaged neurons. Remarkably, the R47H mutation impairs TREM2 detection of lipid ligands. Thus, TREM2 detects damage-associated lipid patterns associated with neurodegeneration, sustaining the microglial response to Aβ accumulation. Copyright © 2015 Elsevier Inc. All rights reserved.
    Full-text · Article · Feb 2015 · Cell
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