TREM2 受甲状腺激素调节，使得 TREM2 途径可以通过甲状腺激素受体的配体进行药物干预。
TREM2 is thyroid hormone regulated making the TREM2 pathway druggable with ligands for thyroid hormone receptor.
机构信息
Department of Chemical Physiology and Biochemistry and Program in Chemical Biology, Oregon Health & Science University, L334, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA.
VA Portland Health Care System, Portland, OR 97239, USA; Department of Neurology, Oregon Health & Science University, Portland, OR 97239, USA.
出版信息
Cell Chem Biol. 2022 Feb 17;29(2):239-248.e4. doi: 10.1016/j.chembiol.2021.07.014. Epub 2021 Aug 9.
Abstract
Triggering receptor expressed on myeloid cells-2 (TREM2) is a cell surface receptor on macrophages and microglia that senses and responds to disease-associated signals to regulate the phenotype of these innate immune cells. The TREM2 signaling pathway has been implicated in a variety of diseases ranging from neurodegeneration in the central nervous system to metabolic disease in the periphery. Here, we report that TREM2 is a thyroid hormone-regulated gene and its expression in macrophages and microglia is stimulated by thyroid hormone and synthetic thyroid hormone agonists (thyromimetics). Our findings report the endocrine regulation of TREM2 by thyroid hormone, and provide a unique opportunity to drug the TREM2 signaling pathway with orally active small-molecule therapeutic agents.
摘要
髓系细胞触发受体 2（TREM2）是巨噬细胞和小胶质细胞表面的受体，可感知和响应与疾病相关的信号，从而调节这些先天免疫细胞的表型。TREM2 信号通路与从中枢神经系统的神经退行性变到外周代谢疾病等多种疾病有关。在这里，我们报告 TREM2 是甲状腺激素调节的基因，其在巨噬细胞和小胶质细胞中的表达受甲状腺激素和合成甲状腺激素激动剂（甲状腺激素模拟物）的刺激。我们的研究结果报告了甲状腺激素对 TREM2 的内分泌调节，并为使用口服活性小分子治疗剂靶向 TREM2 信号通路提供了独特的机会。
相似文献
1
TREM2 is thyroid hormone regulated making the TREM2 pathway druggable with ligands for thyroid hormone receptor.TREM2 受甲状腺激素调节，使得 TREM2 途径可以通过甲状腺激素受体的配体进行药物干预。
Cell Chem Biol. 2022 Feb 17;29(2):239-248.e4. doi: 10.1016/j.chembiol.2021.07.014. Epub 2021 Aug 9.
2
is thyroid hormone regulated making the TREM2 pathway druggable with ligands for thyroid hormone receptor.甲状腺激素是否受到调节，使得TREM2通路可被甲状腺激素受体配体靶向治疗。
bioRxiv. 2021 Jan 27:2021.01.25.428149. doi: 10.1101/2021.01.25.428149.
3
Triggering receptor expressed on myeloid cells-2 expression in the brain is required for maximal phagocytic activity and improved neurological outcomes following experimental stroke.触发受体表达在髓样细胞-2 在大脑中的表达是实验性中风后最大吞噬活性和改善神经功能结局所必需的。
J Cereb Blood Flow Metab. 2019 Oct;39(10):1906-1918. doi: 10.1177/0271678X18817282. Epub 2018 Dec 7.
4
Differential regulation of TREM2 and CSF1R in CNS macrophages in an SIV/macaque model of HIV CNS disease.在 HIV 中枢神经系统疾病的 SIV/猴模型中，中枢神经系统巨噬细胞中 TREM2 和 CSF1R 的差异调节。
J Neurovirol. 2020 Aug;26(4):511-519. doi: 10.1007/s13365-020-00844-1. Epub 2020 Jun 2.
5
Opposing roles of the triggering receptor expressed on myeloid cells 2 and triggering receptor expressed on myeloid cells-like transcript 2 in microglia activation.髓系细胞表达的触发受体2和小胶质细胞中类似髓系细胞表达的触发受体转录本2在小胶质细胞激活中的相反作用。
Neurobiol Aging. 2016 Jun;42:132-41. doi: 10.1016/j.neurobiolaging.2016.03.004. Epub 2016 Mar 16.
6
TREM2-transduced myeloid precursors mediate nervous tissue debris clearance and facilitate recovery in an animal model of multiple sclerosis.在多发性硬化症动物模型中，转导TREM2的髓样前体细胞介导神经组织碎片清除并促进恢复。
PLoS Med. 2007 Apr;4(4):e124. doi: 10.1371/journal.pmed.0040124.
7
TREM2 Promotes Microglial Survival by Activating Wnt/β-Catenin Pathway.TREM2通过激活Wnt/β-连环蛋白通路促进小胶质细胞存活。
J Neurosci. 2017 Feb 15;37(7):1772-1784. doi: 10.1523/JNEUROSCI.2459-16.2017. Epub 2017 Jan 11.
8
TREM2, Microglia, and Neurodegenerative Diseases.TREM2、小胶质细胞与神经退行性疾病
Trends Mol Med. 2017 Jun;23(6):512-533. doi: 10.1016/j.molmed.2017.03.008. Epub 2017 Apr 22.
9
Differential modulation of TREM2 protein during postnatal brain development in mice.小鼠出生后大脑发育过程中 TREM2 蛋白的差异调节。
PLoS One. 2013 Aug 19;8(8):e72083. doi: 10.1371/journal.pone.0072083. eCollection 2013.
10
The Microglial Innate Immune Receptor TREM2 Is Required for Synapse Elimination and Normal Brain Connectivity.小胶质细胞先天免疫受体 TREM2 对于突触消除和正常大脑连接是必需的。
Immunity. 2018 May 15;48(5):979-991.e8. doi: 10.1016/j.immuni.2018.04.016. Epub 2018 May 8.
引用本文的文献
1
Novel Thyroid Hormone Receptor-β Agonist TG68 Exerts Anti-Inflammatory, Lipid-Lowering and Anxiolytic Effects in a High-Fat Diet (HFD) Mouse Model of Obesity.新型甲状腺激素受体-β激动剂TG68在高脂饮食（HFD）肥胖小鼠模型中发挥抗炎、降脂和抗焦虑作用。
Cells. 2025 Apr 11;14(8):580. doi: 10.3390/cells14080580.
2
An adoptive cell therapy with TREM2-overexpressing macrophages mitigates the transition from acute kidney injury to chronic kidney disease.采用过表达TREM2的巨噬细胞进行的过继性细胞疗法可减轻急性肾损伤向慢性肾病的转变。
Clin Transl Med. 2025 Mar;15(3):e70252. doi: 10.1002/ctm2.70252.
3
Association between hypothyroidism and obstructive sleep apnea: a bidirectional Mendelian randomization study combined with the geo database.甲状腺功能减退与阻塞性睡眠呼吸暂停之间的关联：一项结合地理数据库的双向孟德尔随机化研究
Front Neurol. 2024 Dec 10;15:1420391. doi: 10.3389/fneur.2024.1420391. eCollection 2024.
4
Thyroid dysfunction and Alzheimer's disease, a vicious circle.甲状腺功能紊乱与老年痴呆症，恶性循环。
Front Endocrinol (Lausanne). 2024 Feb 14;15:1354372. doi: 10.3389/fendo.2024.1354372. eCollection 2024.
5
Alzheimer risk-increasing TREM2 variant causes aberrant cortical synapse density and promotes network hyperexcitability in mouse models.阿尔茨海默病风险增加的 TREM2 变体导致皮质突触密度异常，并促进小鼠模型中的网络过度兴奋。
Neurobiol Dis. 2023 Oct 1;186:106263. doi: 10.1016/j.nbd.2023.106263. Epub 2023 Aug 15.
6
Thyroid Hormone Transporters MCT8 and OATP1C1 Are Expressed in Pyramidal Neurons and Interneurons in the Adult Motor Cortex of Human and Macaque Brain.甲状腺激素转运体 MCT8 和 OATP1C1 表达于人类和猕猴大脑运动皮层的锥体神经元和中间神经元。
Int J Mol Sci. 2023 Feb 6;24(4):3207. doi: 10.3390/ijms24043207.
7
Some natural hypomethylating agents in food, water and environment are against distribution and risks of COVID-19 pandemic: Results of a big-data research.食品、水和环境中的一些天然去甲基化剂与新冠疫情的分布和风险相悖：一项大数据研究的结果
Avicenna J Phytomed. 2022 May-Jun;12(3):309-324. doi: 10.22038/AJP.2022.19520.
8
Thyroid hormone-dependent oligodendroglial cell lineage genomic and non-genomic signaling through integrin receptors.甲状腺激素依赖的少突胶质细胞谱系通过整合素受体的基因组和非基因组信号传导。
Front Pharmacol. 2022 Sep 5;13:934971. doi: 10.3389/fphar.2022.934971. eCollection 2022.
9
Microglial TYROBP/DAP12 in Alzheimer's disease: Transduction of physiological and pathological signals across TREM2.阿尔茨海默病中的小胶质细胞 TYROBP/DAP12：TREM2 介导的生理和病理信号转导。
Mol Neurodegener. 2022 Aug 24;17(1):55. doi: 10.1186/s13024-022-00552-w.
10
Thyroid hormone signaling in the intestinal stem cells and their niche.肠道干细胞及其龛内的甲状腺激素信号转导。
Cell Mol Life Sci. 2022 Aug 10;79(9):476. doi: 10.1007/s00018-022-04503-y.
本文引用的文献
1
Thyroid hormone and thyromimetics inhibit myelin and axonal degeneration and oligodendrocyte loss in EAE.甲状腺激素和甲状腺刺激素可抑制 EAE 中的髓鞘和轴突变性以及少突胶质细胞丢失。
J Neuroimmunol. 2021 Mar 15;352:577468. doi: 10.1016/j.jneuroim.2020.577468. Epub 2020 Dec 27.
2
A CNS-Targeting Prodrug Strategy for Nuclear Receptor Modulators.一种针对中枢神经系统的前药策略用于核受体调节剂。
J Med Chem. 2020 Sep 10;63(17):9742-9751. doi: 10.1021/acs.jmedchem.0c00868. Epub 2020 Aug 20.
3
TREM2 activation on microglia promotes myelin debris clearance and remyelination in a model of multiple sclerosis.小胶质细胞上的 TREM2 激活促进多发性硬化模型中的髓鞘碎片清除和再髓鞘化。
Acta Neuropathol. 2020 Oct;140(4):513-534. doi: 10.1007/s00401-020-02193-z. Epub 2020 Aug 9.
4
The Physiology, Pathology, and Potential Therapeutic Applications of the TREM2 Signaling Pathway.TREM2 信号通路的生理学、病理学和潜在治疗应用。
Cell. 2020 Jun 11;181(6):1207-1217. doi: 10.1016/j.cell.2020.05.003.
5
Pathological inflammation in patients with COVID-19: a key role for monocytes and macrophages.COVID-19 患者的病理性炎症：单核细胞和巨噬细胞的关键作用。
Nat Rev Immunol. 2020 Jun;20(6):355-362. doi: 10.1038/s41577-020-0331-4. Epub 2020 May 6.
6
COVID-19: consider cytokine storm syndromes and immunosuppression.2019冠状病毒病：考虑细胞因子风暴综合征和免疫抑制。
Lancet. 2020 Mar 28;395(10229):1033-1034. doi: 10.1016/S0140-6736(20)30628-0. Epub 2020 Mar 16.
7
Increased soluble TREM2 in cerebrospinal fluid is associated with reduced cognitive and clinical decline in Alzheimer's disease.脑脊液中可溶性 TREM2 的增加与阿尔茨海默病认知和临床衰退的减少有关。
Sci Transl Med. 2019 Aug 28;11(507). doi: 10.1126/scitranslmed.aav6221.
8
Landscape of Intercellular Crosstalk in Healthy and NASH Liver Revealed by Single-Cell Secretome Gene Analysis.单细胞分泌组基因分析揭示健康和 NASH 肝脏中的细胞间串扰景观。
Mol Cell. 2019 Aug 8;75(3):644-660.e5. doi: 10.1016/j.molcel.2019.07.028.
9
The Emerging Role of Triggering Receptor Expressed on Myeloid Cells 2 as a Target for Immunomodulation in Ischemic Stroke.髓系细胞触发受体 2 在缺血性脑卒中免疫调节中的新兴作用
Front Immunol. 2019 Jul 17;10:1668. doi: 10.3389/fimmu.2019.01668. eCollection 2019.
10
Lipid-Associated Macrophages Control Metabolic Homeostasis in a Trem2-Dependent Manner.脂联巨噬细胞以 Trem2 依赖的方式控制代谢稳态。
Cell. 2019 Jul 25;178(3):686-698.e14. doi: 10.1016/j.cell.2019.05.054. Epub 2019 Jun 27.
Zotero 插件