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      Monoacylglycerol lipase regulates cannabinoid receptor 2-dependent macrophage activation and cancer progression

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          Abstract

          Metabolic reprogramming greatly contributes to the regulation of macrophage activation. However, the mechanism of lipid accumulation and the corresponding function in tumor-associated macrophages (TAMs) remain unclear. With primary investigation in colon cancer and confirmation in other cancer models, here we determine that deficiency of monoacylglycerol lipase (MGLL) results in lipid overload in TAMs. Functionally, macrophage MGLL inhibits CB2 cannabinoid receptor-dependent tumor progression in inoculated and genetic cancer models. Mechanistically, MGLL deficiency promotes CB2/TLR4-dependent macrophage activation, which further suppresses the function of tumor-associated CD8+ T cells. Treatment with CB2 antagonists delays tumor progression in inoculated and genetic cancer models. Finally, we verify that expression of macrophage MGLL is decreased in cancer tissues and positively correlated with the survival of cancer patients. Taken together, our findings identify MGLL as a switch for CB2/TLR4-dependent macrophage activation and provide potential targets for cancer therapy.

          Abstract

          Tumour associated macrophages (TAMs) have an altered lipid metabolism. Here the authors show that downregulation of monoacylglycerols lipase MGLL in TAMs induces lipid accumulation and tumor progression by polarizing TAMs toward tumor-promoting through activation of cannabinoid receptor CB2.

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          Most cited references 37

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          Macrophage activation and polarization: nomenclature and experimental guidelines.

          Description of macrophage activation is currently contentious and confusing. Like the biblical Tower of Babel, macrophage activation encompasses a panoply of descriptors used in different ways. The lack of consensus on how to define macrophage activation in experiments in vitro and in vivo impedes progress in multiple ways, including the fact that many researchers still consider there to be only two types of activated macrophages, often termed M1 and M2. Here, we describe a set of standards encompassing three principles-the source of macrophages, definition of the activators, and a consensus collection of markers to describe macrophage activation-with the goal of unifying experimental standards for diverse experimental scenarios. Collectively, we propose a common framework for macrophage-activation nomenclature. Copyright © 2014 Elsevier Inc. All rights reserved.
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            The future of immune checkpoint therapy.

            Immune checkpoint therapy, which targets regulatory pathways in T cells to enhance antitumor immune responses, has led to important clinical advances and provided a new weapon against cancer. This therapy has elicited durable clinical responses and, in a fraction of patients, long-term remissions where patients exhibit no clinical signs of cancer for many years. The way forward for this class of novel agents lies in our ability to understand human immune responses in the tumor microenvironment. This will provide valuable information regarding the dynamic nature of the immune response and regulation of additional pathways that will need to be targeted through combination therapies to provide survival benefit for greater numbers of patients.
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              TLR4 links innate immunity and fatty acid-induced insulin resistance.

              TLR4 is the receptor for LPS and plays a critical role in innate immunity. Stimulation of TLR4 activates proinflammatory pathways and induces cytokine expression in a variety of cell types. Inflammatory pathways are activated in tissues of obese animals and humans and play an important role in obesity-associated insulin resistance. Here we show that nutritional fatty acids, whose circulating levels are often increased in obesity, activate TLR4 signaling in adipocytes and macrophages and that the capacity of fatty acids to induce inflammatory signaling in adipose cells or tissue and macrophages is blunted in the absence of TLR4. Moreover, mice lacking TLR4 are substantially protected from the ability of systemic lipid infusion to (a) suppress insulin signaling in muscle and (b) reduce insulin-mediated changes in systemic glucose metabolism. Finally, female C57BL/6 mice lacking TLR4 have increased obesity but are partially protected against high fat diet-induced insulin resistance, possibly due to reduced inflammatory gene expression in liver and fat. Taken together, these data suggest that TLR4 is a molecular link among nutrition, lipids, and inflammation and that the innate immune system participates in the regulation of energy balance and insulin resistance in response to changes in the nutritional environment.
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                Author and article information

                Contributors
                yli@tmmu.edu.cn
                yangwei@sibcb.ac.cn
                lianghoujie@sina.com
                hongmingmiao@sina.com
                Journal
                Nat Commun
                Nat Commun
                Nature Communications
                Nature Publishing Group UK (London )
                2041-1723
                3 July 2018
                3 July 2018
                2018
                : 9
                Affiliations
                [1 ]ISNI 0000 0004 1760 6682, GRID grid.410570.7, Department of Biochemistry and Molecular Biology, , Third Military Medical University, ; Chongqing, 400038 China
                [2 ]ISNI 0000 0004 1760 6682, GRID grid.410570.7, Department of Oncology, Southwest Hospital, , Third Military Medical University, ; Chongqing, 400038 China
                [3 ]Department of General Surgery, PLA 324 Hospital, Chongqing, 400020 China
                [4 ]ISNI 0000 0004 1760 6682, GRID grid.410570.7, National Engineering Research Center of Immunological Products, , Third Military Medical University, ; Chongqing, 400038 China
                [5 ]ISNI 0000 0004 1760 6682, GRID grid.410570.7, Institute of Combined Injury, State Key Laboratory of Trauma, Burns and Combined Injury, , Third Military Medical University, ; Chongqing, 400038 China
                [6 ]ISNI 0000 0004 1760 6682, GRID grid.410570.7, Clinical Medicine Research Center & Institute of Cancer, Xinqiao Hospital, , Third Military Medical University, ; Chongqing, 400037 China
                [7 ]ISNI 0000 0000 8877 7471, GRID grid.284723.8, Department of Pathology, School of Basic Medical Sciences & Nanfang Hospital, , Southern Medical University, ; Guangzhou, 510515 China
                Article
                4999
                10.1038/s41467-018-04999-8
                6030061
                29968710
                © The Author(s) 2018

                Open Access This 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 license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license 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 license, visit http://creativecommons.org/licenses/by/4.0/.

                Funding
                Funded by: Youth 1000 Talent Plan (Y.L.)
                Funded by: FundRef https://doi.org/10.13039/501100001809, National Natural Science Foundation of China (National Science Foundation of China);
                Award ID: 31770931
                Award ID: 81672693
                Award Recipient :
                Funded by: 2017A030306030 (W.Y.) from Guangdong Natural Science Funds for Distinguished Young Scholar
                Funded by: Foundation and Frontier Research Project of Chongqing,cstc2017jcyjBX0071
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