Triggering receptor expressed on myeloid cells 2 (TREM2) is known to be involved in the anti-inflammatory response and osteoclast development. However, the role of TREM2 in adipogenesis or obesity has not yet been defined. The effect of TREM2 on adipogenesis and obesity was investigated in TREM2 transgenic (TG) mice on a high-fat diet (HFD). To block TREM2 signaling, a neutralizing fusion protein specific for TREM2 (TREM2-Ig) was used. TG mice were much more obese than wild-type mice after feeding with an HFD, independent of the quantity of food intake. These HFD-fed TG mice manifested adipocyte hypertrophy, glucose and insulin resistance, and hepatic steatosis. The expression of adipogenic regulator genes, such as peroxisome proliferator-activated receptor g and CCAAT/enhancerbinding protein a, was markedly increased in HFD-fed TG mice. Additionally, HFD-fed TG mice exhibited decreased Wnt10b expression and increased GSK-3b (glycogen synthase kinase-3b)-mediated b-catenin phosphorylation. In contrast, the blockade of TREM2 signaling using TREM2-Ig resulted in the inhibition of adipocyte differentiation in vitro and a reduction in body weight in vivo by downregulating the expression of adipogenic regulators. Our data demonstrate that TREM2 promotes adipogenesis and diet-induced obesity by upregulating adipogenic regulators in conjunction with inhibiting the Wnt10b/b-catenin signaling pathway.

TREM2 (triggering receptor expressed on myeloid cells) is involved in the development of malignancies. However, the function of TREM2 in colorectal cancer has not been clearly elucidated. Here, we investigated TREM2 function for the first time in colorectal epithelial cancer cells and demonstrated that TREM2 is a novel tumor suppressor in colorectal carcinoma. Blockade of TREM2 significantly promoted the proliferation of HT29 colorectal carcinoma cells by regulating cell cycle-related factors, such as p53 phosphorylation and p21 and cyclin D1 protein levels. HT29 cell migration was also increased by TREM2 inhibition via MMP9 (matrix metalloproteinase 9) expression upregulation. Furthermore, we found that the tumor suppressor effects of TREM2 were associated with Wnt/β-catenin and extracellular signal-regulated kinase (ERK) signaling. Importantly, the effect of TREM2 in the suppression of tumor development was demonstrated by in vivo and in vitro assays, as well as in human colon cancer patient tissue arrays. Overall, our results identify TREM2 as a potential prognostic biomarker and therapeutic target for colorectal cancer.

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The degradation of p53 by high-risk human papillomavirus (HR-HPV) E6 proteins is recognized as necessary for the immortalization of mammary epithelial cells and the progression of cancer. The HR-HPV type 16 E6 proteins exhibit numerous variants associated with different risk factors for the development of cervical cancer. Two variants of E6 proteins, D25E and L83V, are common in cervical carcinomas among Asian and European populations. In the present study, we compared the effect of two E6 variants on p53 degradation by a prototype E6 protein. We demonstrate that both the D25E and L83V variants downregulate p53 through a ubiquitin-proteasome pathway, and that the effect is very similar to that of the prototype E6 protein. The reduction in the p53 protein levels was induced through the ubiquitin-proteasome pathway via interaction with E6 proteins. The expression of p21 CIP1/WAF1, a downstream molecule of p53, was similarly reduced in both prototype and variant E6 protein-expressing cell lines, leading to aberrant G1/S cell cycle arrest. These results suggest that the natural variants, E6 D25E and L83V, similar to the prototype E6 protein, contribute to tumorigenesis by degrading p53.

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Background Triggering receptor expressed on myeloid cells 2 (TREM2) signaling is considered to regulate anti-inflammatory responses in macrophages, dendritic cell maturation, osteoclast development, induction of obesity, and Alzheimer’s disease pathogenesis. However, little is known regarding the effect of TREM2 on natural killer (NK) cells. Results Here, we demonstrated for the first time that CD3−CD122+NK1.1+ precursor NK (pNK) cells expressed TREM2 and their population increased in TREM2-overexpressing transgenic (TREM2-TG) mice compared with that in female C57BL/6 J wild type (WT) mice. Both NK cell-activating receptors and NK cell-associated genes were expressed at higher levels in various tissues of TREM2-TG mice than in WT mice. In addition, bone marrow-derived hematopoietic stem cells (HSCs) of TREM2-TG mice (TG-HSCs) successfully differentiated into NK cells in vitro, with a higher yield from TG-HSCs than from WT-HSCs. In contrast, TREM2 signaling inhibition by TREM2-Ig or a phosphatidylinositol 3-kinase (PI3K) inhibitor affected the expression of the NK cell receptor repertoire and decreased the expression levels of NK cell-associated genes, resulting in significant impairment of NK cell differentiation. Moreover, in melanoma-bearing WT mice, injection of bone marrow cells from TREM2-TG mice exerted greater antitumor effects than that with cells from WT control mice. Conclusions Collectively, our data clearly showed that TREM2 promoted NK cell development and tumor regression, suggesting TREM2 as a new candidate for cancer immunotherapy.

Background: Triggering receptor expressed on myeloid cells 2 (TREM2) signaling is considered to regulate anti-inflammatory responses in macrophages, dendritic cell maturation, osteoclast development, induction of obesity, and Alzheimer’s disease pathogenesis. However, little is known regarding the effect of TREM2 on natural killer (NK) cells.Results: Here, we demonstrated for the first time that CD3-CD122+NK1.1+ precursor NK (pNK) cells expressed TREM2 and their population increased in TREM2-overexpressing transgenic (TREM2-TG) mice compared with that in female C57BL/6J wild type (WT) mice. Both NK cell-activating receptors and NK cell-associated genes were expressed at higher levels in various tissues of TREM2-TG mice than in WT mice. In addition, bone marrow-derived hematopoietic stem cells (HSCs) of TREM2-TG mice (TG-HSCs) successfully differentiated into NK cells in vitro, with a higher yield from TG-HSCs than from WT-HSCs. In contrast, TREM2 signaling inhibition by TREM2-Ig or a phosphatidylinositol 3-kinase (PI3K) inhibitor affected the expression of the NK cell receptor repertoire and decreased the expression levels of NK cell-associated genes, resulting in significant impairment of NK cell differentiation. Moreover, in melanoma-bearing WT mice, injection of bone marrow cells from TREM2-TG mice exerted greater antitumor effects than that with cells from WT control mice.Conclusions: Collectively, our data clearly showed that TREM2 promoted NK cell development and tumor regression, suggesting TREM2 as a new candidate for cancer immunotherapy.

Intestinal intraepithelial lymphocytes (IELs) are a various community of lymphoid cells located in between the intestinal epithelial cells (IECs) that configure the intestinal mucosal barrier. The epithelial γδT cells act as a major T cell population in epithelia, which is support in tissue homeostasis and repair. However, we found that the γδT cell population was strikingly increased in IELs in TAM receptor-deficient mice. Based on these data, we tested whether this receptor acts as a crucial regulator, which may generate better homing to the intestinal epithelium. We also tested that adoptive transfer of γδT cells to show γδT cell homing to the intestinal epithelium. Our study shows that a key factor in γδT cell homing into the intestinal epithelium, to maintain homeostasis.