TREM⁃2在脓毒症中的作用研究进展

Research progress on the role of TREM-2 in sepsis

摘要

髓样细胞触发受体2（TREM⁃2）是一种免疫球蛋白超家族的跨膜受体，其在髓系细胞表面的表达对调节炎症反应和维持组织稳态至关重要。脓毒症（Sepsis）是感染引起的宿主反应失调，导致危及生命的器官功能损害症候群。TREM⁃2在脓毒症患者中表达水平升高，并与病情严重程度呈负相关。TREM⁃2可通过多种机制参与机体对脓毒症的调控，包括促进细菌吞噬、介导病原体清除、协调Toll样受体（TLR）反应、抑制过度炎症、促进细胞存活和组织修复、调节免疫细胞功能状态以及维持器官稳态。本文综述了TREM⁃2在脓毒症中的作用及其作为治疗靶点的潜力，为脓毒症靶向治疗提供理论依据。

Abstract

Triggering receptor expressed on myeloid cells 2 (TREM⁃2), a transmembrane receptor of the immunoglobulin superfamily, plays a crucial role in regulating inflammatory responses and maintaining tissue homeostasis. Sepsis is a life⁃threatening syndrome characterized by dysregulated host responses to infection, leading to organ dysfunction. In sepsis patients, TREM⁃2 expression is upregulated, with higher levels negatively correlating with disease severity. TREM⁃2 modulates sepsis progression through multiple mechanisms, including enhancing bacterial phagocytosis and pathogen clearance, suppressing Toll⁃like receptor (TLR) ⁃ mediated inflammation, promoting cell survival and tissue repair, and regulating immune cell functional states. An emerging and critical insight is the context⁃dependent duality of TREM⁃2 signaling: although it is predominantly protective, recent studies suggest that under certain conditions it may exacerbate inflammatory injury, highlighting the complexity of its regulatory network. In conclusion, this review summarizes the role of TREM⁃2 in sepsis and highlights its potential as a therapeutic target, providing a theoretical basis for targeted sepsis therapies.

关键词

脓毒症 / 髓样细胞触发受体2 / 巨噬细胞 / 炎症反应

Key words

Sepsis / Triggering Receptor Expressed on Myeloid Cells 2 / Macrophage / Inflammatory Response

参考文献

[1] SRZIĆ I, NESEK ADAM V, TUNJIĆ PEJAK D. Sepsis definition: What's new in the treatment guidelines[J]. Acta Clin Croat, 2022, 61(Suppl 1): 67-72.

[2] RUDD K E, JOHNSON S C, AGESA K M, et al. Global, regional, and national sepsis incidence and mortality, 1990—2017: Analysis for the Global Burden of Disease Study[J]. Lancet, 2020, 395(10219): 200-211.

[3] SU P, ZHANG J B, WU J X, et al. TREM2 expression on the microglia resolved lead exposure—induced neuroinflammation by promoting anti—inflammatory activities[J]. Ecotoxicol Environ Saf, 2023, 260: 115058.

[4] CHEN Q X, ZHANG K, JIN Y, et al. Triggering receptor expressed on myeloid cells—2 protects against polymicrobial sepsis by enhancing bacterial clearance[J]. Am J Respir Crit Care Med, 2013, 188(2): 201-212.

[5] YANG S Y, YANG Y, WANG F F, et al. TREM2 dictates antibacterial defense and viability of bone marrow—derived macrophages during bacterial infection[J]. Am J Respir Cell Mol Biol, 2021, 65(2): 176-188.

[6] SINGH H, RAI V, NOOTI S K, et al. Novel ligands and modulators of triggering receptor expressed on myeloid cells receptor family: 2015—2020 updates[J]. Expert Opin Ther Pat, 2021, 31(6): 549-561.

[7] ULLAND T K, COLONNA M. TREM2: A key player in microglial biology and Alzheimer disease[J]. Nat Rev Neurol, 2018, 14(11): 667-675.

[8] DECZKOWSKA A, WEINER A, AMIT I. The physiology, pathology, and potential therapeutic applications of the TREM2 signaling pathway[J]. Cell, 2020, 181(6): 1207-1217.

[9] KOBER D L, BRETT T J. TREM2—ligand interactions in health and disease[J]. J Mol Biol, 2017, 429(11): 1607-1629.

[10] HAURE—MIRANDE J V, AUDRAIN M, EHRLICH M E, et al. Microglial TYROBP/DAP12 in Alzheimer's disease: Transduction of physiological and pathological signals across TREM2[J]. Mol Neurodegener, 2022, 17(1): 55.

[11] KONISHI H, KIYAMA H. Microglial TREM2/DAP12 signaling: A double—edged sword in neural diseases[J]. Front Cell Neurosci, 2018, 12: 206.

[12] GRATUZE M, LEYNS C E G, HOLTZMAN D M. New insights into the role of TREM2 in Alzheimer's disease[J]. Mol Neurodegener, 2018, 13(1): 66.

[13] FILIPELLO F, GOLDSBURY C, YOU S F, et al. Soluble TREM2: Innocent bystander or active player in neurological diseases? [J]. Neurobiol Dis, 2022, 165: 105630.

[14] FEUERBACH D, SCHINDLER P, BARSKE C, et al. ADAM17 is the main sheddase for the generation of human triggering receptor expressed in myeloid cells (hTREM2) ectodomain and cleaves TREM2 after Histidine 157[J]. Neurosci Lett, 2017, 660: 109-114.

[15] WU K Y, BYERS D E, JIN X H, et al. TREM—2 promotes macrophage survival and lung disease after respiratory viral infection[J]. J Exp Med, 2015, 212(5): 681-697.

[16] ORHUN G, ESEN F, YILMAZ V, et al. Elevated sTREM2 and NFL levels in patients with sepsis associated encephalopathy[J]. Int J Neurosci, 2023, 133(3): 327-333.

[17] HOLTZMAN M J, BYERS D E, ALEXANDER—BRETT J, et al. The role of airway epithelial cells and innate immune cells in chronic respiratory disease[J]. Nat Rev Immunol, 2014, 14(10): 686-698.

[18] WANG S T, SUDAN R, PENG V, et al. TREM2 drives microglia response to amyloid—β via SYK—dependent and—independent pathways[J]. Cell, 2022, 185(22): 4153-4169.e19.

[19] KLEINBERGER G, BRENDEL M, MRACSKO E, et al. The FTD—like syndrome causing TREM2 T66M mutation impairs microglia function, brain perfusion, and glucose metabolism[J]. EMBO J, 2017, 36(13): 1837-1853.

[20] WANG Y, CAO C, ZHU Y T, et al. TREM2/β—catenin attenuates NLRP3 inflammasome—mediated macrophage pyroptosis to promote bacterial clearance of pyogenic bacteria[J]. Cell Death Dis, 2022, 13(9): 771.

[21] HU L F, LIU J, PENG J, et al. TREM2 alleviates neuroinflammation by maintaining cellular metabolic homeostasis and mitophagy activity during early inflammation[J]. Diseases, 2025, 13(2): 60.

[22] ZHOU Y S, YU G R, LI H. Hancinone possesses potentials on increasing the ability of HMC3 cells to phagocytosis of Aβ1—42 via TREM2/Syk/PI3K/AKT/mTOR signaling pathway[J]. PLoS One, 2025, 20(5): e0324202.

[23] PERUGORRIA M J, OLAIZOLA P, LABIANO I, et al. Wnt—β—catenin signalling in liver development, health and disease[J]. Nat Rev Gastroenterol Hepatol, 2019, 16(2): 121-136.

[24] ZHENG H H, JIA L, LIU C C, et al. TREM2 promotes microglial survival by activating Wnt/β—catenin pathway[J]. J Neurosci, 2017, 37(7): 1772-1784.

[25] SINGER M, DEUTSCHMAN C S, SEYMOUR C W, et al. The third international consensus definitions for sepsis and septic shock (sepsis—3) [J]. JAMA, 2016, 315(8): 801-810.

[26] COLONNA M. The biology of TREM receptors[J]. Nat Rev Immunol, 2023, 23(9): 580-594.

[27] LI C X, ZHAO B, LIN C Z, et al. TREM2 inhibits inflammatory responses in mouse microglia by suppressing the PI3K/NF—κB signaling[J]. Cell Biol Int, 2019, 43(4): 360-372.

[28] RUGANZU J B, ZHENG Q Z, WU X Y, et al. TREM2 overexpression rescues cognitive deficits in APP/PS1 transgenic mice by reducing neuroinflammation via the JAK/STAT/SOCS signaling pathway[J]. Exp Neurol, 2021, 336: 113506.

[29] IIZASA E, CHUMA Y, UEMATSU T, et al. TREM2 is a receptor for non—glycosylated mycolic acids of mycobacteria that limits anti—mycobacterial macrophage activation[J]. Nat Commun, 2021, 12(1): 2299.

[30] LI D D, PAN L Y, CHEN M J, et al. TREM2 protects against LPS—induced murine acute lung injury through suppressing macrophage ferroptosis[J]. Int Immunopharmacol, 2025, 150: 114247.

[31] SHU J X, LIANG J B, ZENG L D, et al. TREM2 drives neutrophil extracellular traps—induced dendritic cell maturation and contributes to lupus progression[J]. Adv Sci, 2025: e08938.

[32] GALLO C, MANZO E, BARRA G, et al. Sulfavant A as the first synthetic TREM2 ligand discloses a homeostatic response of dendritic cells after receptor engagement[J]. Cell Mol Life Sci, 2022, 79(7): 369.

[33] ZHENG J Y, WANG L X, ZHAO S Y, et al. TREM2 mediates MHC Ⅱ—associated CD4⁺T—cell response against gliomas[J]. Neuro Oncol, 2024, 26(5): 811-825.

[34] WU Y J, WANG M N, YIN H, et al. TREM—2 is a sensor and activator of T cell response in SARS—CoV—2 infection[J]. Sci Adv, 2021, 7(50): eabi6802.

[35] PROVERA A, RAMAVATH N N, GADIPUDI L L, et al. Role of the co—stimulatory molecule inducible T—cell co—stimulator ligand (ICOSL) in the progression of experimental metabolic dysfunction—associated steatohepatitis[J]. Front Immunol, 2023, 14: 1290391.

[36] WU Y J, WU M H, MING S Q, et al. TREM—2 promotes Th1 responses by interacting with the CD3ζ—ZAP70 complex following Mycobacterium tuberculosis infection[J]. J Clin Invest, 2021, 131(17): e137407.

[37] ZHANG K, WANG Y, CHEN S Y, et al. TREM2(hi) resident macrophages protect the septic heart by maintaining cardiomyocyte homeostasis[J]. Nat Metab, 2023, 5(1): 129-146.

[38] HERNÁNDEZ—ALVAREZ M I, SEBASTIÁN D, VIVES S, et al. Deficient endoplasmic reticulum—mitochondrial phosphatidylserine transfer causes liver disease[J]. Cell, 2019, 177(4): 881-895.e17.

[39] HOU J C, ZHANG J, CUI P, et al. TREM2 sustains macrophage—hepatocyte metabolic coordination in nonalcoholic fatty liver disease and sepsis[J]. J Clin Invest, 2021, 131(4): e135197.

[40] VERHEUL T C J, VAN HIJFTE L, PERENTHALER E, et al. The why of YY1: Mechanisms of transcriptional regulation by Yin Yang 1[J]. Front Cell Dev Biol, 2020, 8: 592164.

[41] LI X, XIAO C, YUAN J, et al. Rhein—attenuates LPS—induced acute lung injury via targeting NFATc1/Trem2 axis[J]. Inflamm Res, 2023, 72(6): 1237-1255.

[42] LIM G B. Cardiac—resident macrophages protect against sepsis—induced cardiomyopathy[J]. Nat Rev Cardiol, 2023, 20(3): 141.

[43] PINTO B B, DYSON A, UMBRELLO M, et al. Improved survival in a long—term rat model of sepsis is associated with reduced mitochondrial calcium uptake despite increased energetic demand[J]. Crit Care Med, 2017, 45(8): e840-e848.

[44] NICOLÁS—ÁVILA J Á, HIDALGO A. TREM2(+) macrophages are guardians of the heart[J]. Nat Metab, 2023, 5(1): 13-15.

[45] STRNAD P, TACKE F, KOCH A, et al. Liver: Guardian, modifier and target of sepsis[J]. Nat Rev Gastroenterol Hepatol, 2017, 14(1): 55-66.

[46] JEPPESEN D K, FENIX A M, FRANKLIN J L, et al. Reassessment of exosome composition[J]. Cell, 2019, 177(2): 428-445.e18.

[47] TERRASINI N, LIONETTI V. Exosomes in critical illness[J]. Crit Care Med, 2017, 45(6): 1054-1060.

[48] YING W, RIOPEL M, BANDYOPADHYAY G, et al. Adipose tissue macrophage—derived exosomal miRNAs can modulate in vivo and in vitro insulin sensitivity[J]. Cell, 2017, 171(2): 372-384.e12.

[49] LIU Y J, LIU L J, ZHANG J. Protective role of matrine in sepsis—associated cardiac dysfunction through regulating the lncRNA PTENP1/miR—106b—5p axis[J]. Biomed Pharmacother, 2021, 134: 111112.

[50] YE H, ZHAI Q, FANG P, et al. Triggering receptor expressed on myeloid Cells—2 (TREM2) inhibits steroidogenesis in adrenocortical cell by macrophage—derived exosomes in lipopolysaccharide—induced septic shock[J]. Mol Cell Endocrinol, 2021, 525: 111178.

[51] VAIDYA A, FINDLING J, BANCOS I. Adrenal insufficiency in adults: A review[J]. JAMA, 2025, 334(8): 714-725.

[52] XU Y Z, PATTERSON M T, DOLFI B, et al. Adrenal gland macrophages regulate glucocorticoid production through TREM2 and TGF—β[J]. JCI Insight, 2024, 9(14): e174746.

[53] GAO Q Z, HERNANDES M S. Sepsis—associated encephalopathy and blood—brain barrier dysfunction[J]. Inflammation, 2021, 44(6): 2143-2150.

[54] ZHANG J W, LIU Y, ZHENG Y L, et al. TREM—2—p38 MAPK signaling regulates neuroinflammation during chronic cerebral hypoperfusion combined with diabetes mellitus[J]. J Neuroinflammation, 2020, 17(1): 2.

[55] WU S R, WANG H M, LI Y J, et al. Transcription factor YY1 promotes cell proliferation by directly activating the pentose phosphate pathway[J]. Cancer Res, 2018, 78(16): 4549-4562.

[56] PENG L S, XU Y, WANG Q S. YY1 promotes microglia M2 polarization through the miR—130a—3p/TREM—2 axis to alleviate sepsis—associated encephalopathy[J]. Shock, 2022, 58(2): 128-136.

[57] ZHOU F, MEI J T, HAN X G, et al. Kinsenoside attenuates osteoarthritis by repolarizing macrophages through inactivating NF—κB/MAPK signaling and protecting chondrocytes[J]. Acta Pharm Sin B, 2019, 9(5): 973-985.

[58] XU Y, SHEN J, RAN Z H. Emerging views of mitophagy in immunity and autoimmune diseases[J]. Autophagy, 2020, 16(1): 3-17.

[59] ZHANG L, WANG Y, WU G R, et al. Macrophages: Friend or foe in idiopathic pulmonary fibrosis? [J]. Respir Res, 2018, 19(1): 170.

[60] WITHEREL C E, ABEBAYEHU D, BARKER T H, et al. Macrophage and fibroblast interactions in biomaterial—mediated fibrosis[J]. Adv Healthc Mater, 2019, 8(4): 1801451.

[61] LEE J W, CHUN W, LEE H J, et al. The role of macrophages in the development of acute and chronic inflammatory lung diseases[J]. Cells, 2021, 10(4): 897.

[62] HE Y Q, ZHOU C C, YU L Y, et al. Natural product derived phytochemicals in managing acute lung injury by multiple mechanisms[J]. Pharmacol Res, 2021, 163: 105224.

[63] ZHOU Y Y, GAO C F, VONG C T, et al. Rhein regulates redox—mediated activation of NLRP3 inflammasomes in intestinal inflammation through macrophage—activated crosstalk[J]. Br J Pharmacol, 2022, 179(9): 1978-1997.

[64] MING S Q, LI X Y, XIAO Q, et al. TREM2 aggravates sepsis by inhibiting fatty acid oxidation via the SHP1/BTK axis[J]. J Clin Invest, 2024, 135(1): e159400.

基金资助

新发突发与重大传染病防控国家科技重大专项(2025ZD01902600)

国家自然科学基金面上项目(82272226)

国家自然科学基金面上项目(82572461)

国家自然科学基金青年项目(82502662)