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      TREM2 promotes natural killer cell development in CD3 CD122 +NK1.1 + pNK cells

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          Abstract

          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.

          Supplementary Information

          The online version contains supplementary material available at 10.1186/s12865-021-00420-0.

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          Most cited references61

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          Monocyte and macrophage heterogeneity.

          Heterogeneity of the macrophage lineage has long been recognized and, in part, is a result of the specialization of tissue macrophages in particular microenvironments. Circulating monocytes give rise to mature macrophages and are also heterogeneous themselves, although the physiological relevance of this is not completely understood. However, as we discuss here, recent studies have shown that monocyte heterogeneity is conserved in humans and mice, allowing dissection of its functional relevance: the different monocyte subsets seem to reflect developmental stages with distinct physiological roles, such as recruitment to inflammatory lesions or entry to normal tissues. These advances in our understanding have implications for the development of therapeutic strategies that are targeted to modify particular subpopulations of monocytes.
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            Cutting edge: inflammatory responses can be triggered by TREM-1, a novel receptor expressed on neutrophils and monocytes.

            We have identified new activating receptors of the Ig superfamily expressed on human myeloid cells, called TREM (triggering receptor expressed on myeloid cells). TREM-1 is selectively expressed on blood neutrophils and a subset of monocytes and is up-regulated by bacterial LPS. Engagement of TREM-1 triggers secretion of IL-8, monocyte chemotactic protein-1, and TNF-alpha and induces neutrophil degranulation. Intracellularly, TREM-1 induces Ca2+ mobilization and tyrosine phosphorylation of extracellular signal-related kinase 1 (ERK1), ERK2 and phospholipase C-gamma. To mediate activation, TREM-1 associates with the transmembrane adapter molecule DAP12. Thus, TREM-1 mediates activation of neutrophil and monocytes, and may have a predominant role in inflammatory responses.
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              Cutting edge: TREM-2 attenuates macrophage activation.

              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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                Author and article information

                Contributors
                kanghs@jnu.ac.kr
                eunmi.kim@kitox.re.kr
                Journal
                BMC Immunol
                BMC Immunol
                BMC Immunology
                BioMed Central (London )
                1471-2172
                12 May 2021
                12 May 2021
                2021
                : 22
                : 30
                Affiliations
                [1 ]GRID grid.419585.4, ISNI 0000 0004 0647 9913, Chemicals Registration & Evaluation Team, , National Institute of Environmental Research, ; Hwangyeong-ro 42, Seo-gu, Incheon, 22689 Korea
                [2 ]GRID grid.496160.c, ISNI 0000 0004 6401 4233, Medical Device Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, ; 80 Cheombok-ro, Dong-gu, Daegu, 41061 Korea
                [3 ]GRID grid.14005.30, ISNI 0000 0001 0356 9399, School of Biological Sciences and Technology, Chonnam National University, ; 77 Yongbong-ro, Buk-gu, Gwangju, 61186 Republic of Korea
                [4 ]GRID grid.418980.c, ISNI 0000 0000 8749 5149, Herbal Medicine Research Division, , Korea Institute of Oriental Medicine, ; 461-24 Jeonmin-dong, Yuseong-gu, Daejeon, 34054 Korea
                [5 ]GRID grid.412003.4, ISNI 0000 0000 9692 3002, Department of Nursing, , Nambu University, ; 23 Chumdan Jungang-ro, Gwangsan-gu, Gwangju, 62271 Korea
                [6 ]GRID grid.418982.e, ISNI 0000 0004 5345 5340, Department of Predictive Toxicology, , Korea Institute of Toxicology, ; 141 Gajeong-ro, Yuseong-gu, Daejeon, 34114 Republic of Korea
                Article
                420
                10.1186/s12865-021-00420-0
                8114489
                33980160
                bb75d3fd-c2f3-404f-95db-3d41a3b0b826
                © The Author(s) 2021

                Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

                History
                : 15 December 2020
                : 6 April 2021
                Categories
                Research
                Custom metadata
                © The Author(s) 2021

                Immunology
                trem2,natural killer cell,nk cell development,cancer immunotherapy
                Immunology
                trem2, natural killer cell, nk cell development, cancer immunotherapy

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