Cutting Edge: TREM-2 Attenuates Macrophage Activation

Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
The Journal of Immunology (Impact Factor: 4.92). 10/2006; 177(6):3520-4. DOI: 10.4049/jimmunol.177.6.3520
Source: PubMed


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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    • "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), (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.
    Cell 02/2015; DOI:10.1016/j.cell.2015.01.049 · 32.24 Impact Factor
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    • "However, the molecular mechanisms underlying this observation still remain unclear. In view of the fact that TLR had a major role in mediating Abtriggered microglial proinflammatory responses (Jin et al, 2008; Liu et al, 2012), several lines of evidence suggested that TREM2 was a negative regulator of TLR signaling in myeloid cells (Hamerman et al, 2006; Ito and Hamerman, 2012; Turnbull et al, 2006); it is likely that the TREM2 attenuated Ab 1–42 -triggered proinflammatory responses through inhibition of TLR signaling and functions. Moreover , we found that the modulation of TREM2 on microglial functions under AD context was dependent on it adaptor protein DAP12, as knockdown of DAP12 in microglia fully abolished the modulative effects of TREM2 on Ab 1–42 phagocytosis and Ab 1–42 -induced proinflammatory responses . "
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    ABSTRACT: Triggering receptor expressed on myeloid cells 2 gene (TREM2) is a recently identified susceptibility gene for Alzheimer's disease (AD), since its low-frequency variants increase the risk of this disease with an odds ratio similar to that of one APOE ɛ4 allele. To date, the expression and biological functions of TREM2 under AD context remain largely unknown. Using APPswe/PS1dE9 mice, a transgenic model of AD, we showed that TREM2 was up-regulated in microglia during disease progression. For the first time, we provided in vitro and in vivo evidence that this up-regulation was attributed to the increased amyloid-β (Aβ) 1-42 levels in brain. By knockdown and overexpression of TREM2 in cultured primary microglia, we revealed that TREM2 modulated microglial functions under AD context, as it facilitated Aβ1-42 phagocytosis and inhibited Aβ1-42-triggered pro-inflammatory responses. Meanwhile, this modulation was depended on DAP12, the adapter protein of TREM2. More importantly, overexpression of TREM2 in brain of APPswe/PS1dE9 mice markedly ameliorated AD-related neuropathology including Aβ deposition, neuroinflammation and neuronal and synaptic losses, which was accompanied by an improvement in spatial cognitive functions. Taken together, our data suggest that the up-regulation of TREM2 serves as a compensatory response to Aβ1-42 and subsequently protects against AD progression via modulation of microglia functions. These findings provide insights into the role of TREM2 in AD pathogenesis, and highlight TREM2 as a potential therapeutic target for this disease.Neuropsychopharmacology accepted article preview online, 22 July 2014; doi:10.1038/npp.2014.164.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 07/2014; 39(13). DOI:10.1038/npp.2014.164 · 7.05 Impact Factor
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    • "Despite the reduction in plaque-associated microglia, we did not observe any statistically significant difference in the expression of inflammatory cytokines or genes associated with microglial activation in TREM2 Het and TREM2 WT mice in either 3-month or 7-month old animals. TREM2-DAP12 signaling inhibits Toll-like receptor (TLR)-dependent cytokine production and bone marrow derived macrophages from TREM2 KO mice exhibit increased expressed inflammatory cytokine production in response to microbial stimulation [29]. Similarly, knockdown of TREM2 expression in microglia co-cultured with apoptotic neurons resulted in increased production of TNFα and NOS2 [8]. "
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    ABSTRACT: Background Recent genome-wide association studies linked variants in TREM2 to a strong increase in the odds of developing Alzheimer’s disease. The mechanism by which TREM2 influences the susceptibility to Alzheimer’s disease is currently unknown. TREM2 is expressed by microglia and is thought to regulate phagocytic and inflammatory microglial responses to brain pathology. Given that a single allele of variant TREM2, likely resulting in a loss of function, conferred an increased risk of developing Alzheimer’s disease, we tested whether loss of one functional trem2 allele would affect Aβ plaque deposition or the microglial response to Aβ pathology in APPPS1-21 mice. Results There was no significant difference in Aβ deposition in 3-month old or 7-month old APPPS1-21 mice expressing one or two copies of trem2. However, 3-month old mice with one copy of trem2 exhibited a marked decrease in the number and size of plaque-associated microglia. While there were no statistically significant differences in cytokine levels or markers of microglial activation in 3- or 7-month old animals, there were trends towards decreased expression of NOS2, C1qa, and IL1a in 3-month old TREM2+/− vs. TREM2+/+ mice. Conclusions Loss of a single copy of trem2 had no effect on Aβ pathology, but altered the morphological phenotype of plaque-associated microglia. These data suggest that TREM2 is important for the microglial response to Aβ deposition but that a 50% decrease inTREM2 expression does not affect Aβ plaque burden.
    Molecular Neurodegeneration 06/2014; 9(1):20. DOI:10.1186/1750-1326-9-20 · 6.56 Impact Factor
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