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.

Graphical abstract

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

脓毒症是一种由感染引发的致命性全身炎症反应综合征，常导致多器官功能障碍^［1］，是全球主要的公共卫生负担，年死亡人数高达约1 100万^［2］。其高死亡率驱使人们不断探寻新的治疗靶点。髓样细胞触发受体‑2（triggering receptor expressed on myeloid cells 2，TREM‑2）作为一种关键的免疫调节受体^［3］，在脓毒症中表达上调，且其水平与疾病严重程度呈负相关^［4‑5］。这提示其在脓毒症病理过程中可能起保护作用。因此，深入探讨TREM‑2在脓毒症中的作用对于开发脓毒症新疗法具有重要意义。本综述旨在总结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。

1 TREM‑2概述

TREM是髓系细胞表面表达的一类免疫球蛋白超家族（Ig‑SF）受体，迄今发现至少3个TREM家族成员，按其被发现的顺序依次命名为TREM‑1、TREM‑2、TREM‑3等^［6］。TREM‑2主要表达于树突状细胞、巨噬细胞等髓系细胞表面^［7］，由一个用于识别配体（如细菌产物、脂蛋白等）的胞外Ⅴ型免疫球蛋白结构域、跨膜区和一个缺乏信号基序的短胞质尾部构成^［8‑9］（图1）。由于TREM‑2的短胞质尾部缺乏信号传导和运输基序，TREM‑2在与配体结合后产生的跨膜信号传递需要DNAX活化蛋白12（DNAX‑activating protein of 12 kU，DAP12）参与^［10］。当配体与TREM‑2结合后，跨膜区电荷相互作用会募集DAP12，导致DAP12胞内段的免疫受体酪氨酸基于激活模体（immunoreceptor tyrosine‑based activation motif，ITAM）磷酸化，进而招募并激活脾酪氨酸激酶（spleen tyrosine kinase，SYK）。SYK的激活可启动下游包括PI3K/AKT、PLCγ和ERK在内的多条信号通路，最终调控细胞的吞噬、存活及炎症因子释放等生物学行为^{［11‑12］}。

TREM‑2可被ADAM蛋白酶在H157S158肽键处剪切，产生可溶性形式的TREM‑2（soluble TREM‑2，sTREM‑2）^［13］。当受到细菌、干扰素‑γ或脂多糖的刺激时，ADAM也可以进一步切割TREM‑2的跨膜部分，使髓系细胞膜表面的TREM‑2表达迅速下降，从而阻断TREM‑2信号传导，间接发挥TREM‑2抑制剂的作用^［14］。研究^［15］表明sTREM‑2具有双重功能：一方面可通过激活ERK1/2和PI3K‑AKT通路促进细胞存活。另一方面可作为脓毒症相关脑病等疾病的生物标志物，其水平与认知功能下降相关^［16］。在炎症状态下，sTREM‑2的产生会降低细胞TREM‑2的表达，从而调节信号传导强度^［17］。

2　TREM‑2调控脓毒症

2.1　增强病原体清除与维护组织完整性

作为巨噬细胞表面的吞噬受体，TREM‑2直接识别并介导对细菌、凋亡细胞及细胞碎片的吞噬，是启动免疫清除的第一道环节^［8］。研究^［18］表明TREM‑2在不具有吞噬能力的细胞中过表达，可诱导细菌、脂蛋白和细胞碎片等的吞噬，比如在中国仓鼠卵巢细胞中TREM‑2通过TREM‑2/DAP12信号复合体招募并磷酸化SYK，进而启动PI3K/AKT与PKC等下游通路，促进细菌的结合和吞噬。同样在具有吞噬作用的细胞中，TREM‑2表达缺失或减少也会减少凋亡细胞、细胞碎片、细菌等的吞噬^［19］。

这一介导病原体吞噬的过程不仅增强了吞噬体的成熟，更关键的是能激活NADPH氧化酶2（NADPH oxidase 2，NOX2），促使吞噬体内产生活性氧（reactive oxygen species，ROS），直接杀伤如大肠杆菌、铜绿假单胞菌和鼠伤寒沙门氏菌等病原体^{［20‑21］}。此外，TREM‑2通过稳定β‑连环蛋白（β‑catenin），有效抑制由线粒体ROS驱动的NLRP3炎症小体活化和caspase‑1介导的细胞焦亡，从而在清除感染源的同时限制炎症性细胞死亡带来的二次损伤^{［5， 20］}。临床研究^［5］证明细菌性脓毒症患者TREM‑2表达与NOX2浓度呈正相关，与caspase‑1阳性单核细胞数量呈负相关，并且TREM‑2浓度与脓毒症的严重程度呈负相关。

在组织修复层面，TREM‑2与巨噬细胞集落刺激因子（colony‑stimulating factor 1，CSF‑1）信号协同，通过SYK‑PI3K/AKT轴上调抗凋亡蛋白（如BCL‑2）的表达，促进巨噬细胞在炎症环境中的存活^［22］。此外，TREM‑2可激活Wnt/β‑catenin通路，促进Wnt蛋白分泌，抑制β‑catenin的降解，调控修复相关基因的表达，为组织再生创造有利的微环境^{［23‑24］}。

2.2　负向调控过度炎症反应

脓毒症中失控的全身炎症反应是导致器官损伤的关键^［25］。TREM‑2可以通过多种通路负向调节炎症反应。第一，在脂多糖的刺激下，TREM‑2能通过其衔接蛋白DAP12的ITAM结构域募集对接蛋白3（docking protein 3，DOK3）。磷酸化的DOK3与Grb2‑SOS1结合，负向调控Ras‑ERK MAPK信号通路，从而抑制TNF‑α、IL‑6等促炎因子^{［22， 26］}。第二，TREM‑2信号能直接或间接抑制PI3K/AKT/IκB kinase通路，减少NF‑κB的核转位，从转录源头遏制炎症风暴^［27］。第三，TREM‑2还可诱导细胞因子信号抑制因子（suppressor of cytokine signaling，SOCS）家族蛋白的表达，通过JAK/STAT/SOCS通路反馈性抑制细胞因子信号，形成抗炎闭环^［28］。最后，TREM‑2的缺失会导致感染模型中趋化因子（如CXCL1、CXCL2）水平升高，进而引起中性粒细胞过度浸润至组织，加重炎症损伤，这进一步体现了TREM‑2在炎症细胞募集层面的全局调控作用^{［29‑30］}。

2.3　桥接并调控适应性免疫应答

TREM‑2通过调控抗原提呈细胞的功能，桥接固有免疫与适应性免疫。在树突状细胞中，TREM‑2/DAP12信号通过SYK激活ERK‑MAPK通路^［31］，不仅促进细胞存活与成熟，更显著上调主要组织相容性复合体Ⅱ类（major histocompatibility complex Ⅱ，MHC Ⅱ）分子和共刺激分子CD86/CD40的表达^［32］，从而极大地增强了树突状细胞向初始CD4⁺ T细胞提呈抗原的能力^［33］。缺乏TREM‑2将导致T细胞活化不足，削弱机体清除病原体的能力^{［34‑35］}。研究^［34］发现，在MHV‑A59小鼠模型中，敲除TREM‑2基因的小鼠比野生型小鼠表现出更严重的肺损伤、更高的病毒负荷以及更低水平的细胞因子IFN‑γ、TNF‑α。更为精准的是，TREM‑2本身亦可在T细胞上表达，并通过与T细胞受体（T cell receptor，TCR）信号协作，促进ZAP70‑STAT1/STAT4信号轴的激活，这有利于促炎的Th1型免疫应答的分化，增强IFN‑γ的产生，从而更有效地对抗细胞内病原体感染^［36］。这表明TREM‑2通过多细胞、多途径协同，确保适应性免疫应答的适时、适度和有效。

3 TREM‑2维持脓毒症器官代谢稳态

脓毒症导致的多器官功能衰竭是患者死亡的主要原因。除系统性免疫调节外，TREM‑2通过在关键器官的组织巨噬细胞中特异性表达，参与维持局部稳态，对改善预后具有重要意义^{［37‑41］}。

3.1　维持心脏代谢和功能

脓毒症会引起心肌细胞功能失调线粒体的积累，而游离线粒体和线粒体DNA（mitochondria DNA，mtDNA）会引起心脏损伤^［42］。并且，线粒体功能障碍与脓毒症预后不良直接相关^［43］，因此维持心肌线粒体稳态对于脓毒症心肌病（sepsis‑induced cardiomyopathy，SICM）至关重要。Mac1是一种常驻于心肌的巨噬细胞，可以通过吞噬和清除心肌细胞释放的功能失调的线粒体来恢复心肌线粒体稳态^{［42， 44］}。但如果Mac1缺乏TREM‑2表达，其自我更新能力将会降低，进而导致受损线粒体在心肌中堆积，心脏组织炎症反应过度，心功能障碍加剧，死亡率升高^{［37， 42］}。研究^［37］报道，移植高表达TREM‑2的巨噬细胞（TREM‑2hi Mac1）可以改善心脏损伤、炎症及线粒体损伤，提升ATP水平并降低乳酸堆积，并且心包内注射TREM‑2hi Mac1细胞可预防SICM的发生和发展。

3.2　协调肝脏细胞间代谢

脓毒症容易导致肝脏损伤，特别是在患者存在既往肝损伤病史的情况下^［45］。外泌体（exosome，Exos）是小的细胞外囊泡，可转移分子成分，如蛋白质、DNA和miRNAs等^［46］，在内源性分子的递送中调节受体细胞的基因表达和相关的生理和病理生理过程^［47］。不表达TREM‑2的巨噬细胞释放的外泌体会损伤肝细胞的线粒体结构和能量供应，进而加重非酒精性脂肪肝相关脓毒症^［48］。这可能与Exos含有的大量miR‑106b‑5p阻断线粒体融合蛋白2相关^{［38， 49］}。相反，肝巨噬细胞中TREM‑2过表达可以通过改善肝脏能量供应来降低脓毒症死亡率^［39］。

3.3　精细调控肾上腺应激轴

TREM‑2还参与对神经内分泌应激反应的精细调控。研究^［50］表明，TREM‑2基因敲除的巨噬细胞能通过外泌体向肾上腺皮质细胞传递信号，促进类固醇生成酶的表达，导致皮质醇的过度合成。这种失控的免疫‑肾上腺串扰可能增加死亡风险^［51］，而正常的TREM‑2功能则有助于限制过度的糖皮质激素反应，维持内环境稳定^{［50， 52］}。

3.4　调控脓毒症脑病，减轻脑部炎症

在脓毒症相关脑病中，M1极化的小胶质细胞具有破坏性，会分泌促炎细胞因子^［53］。TREM‑2过表达可以抑制高糖低氧状态下小胶质细胞释放促炎因子，而TREM‑2沉默可促进促炎因子释放^［54］。研究^［55］发现阴阳1（Yin Yang 1，YY1）是一种多功能转录因子，可以通过抑制miR‑130a‑3p启动子的活性，上调TREM‑2的表达，从而促进小胶质细胞M2极化，减轻炎症，在脓毒症的发展中起关键作用^{［40， 56］}。

3.5　抑制NF‑κB活化，减轻急性肺损伤

脓毒症相关的急性肺损伤（acute lung injury，ALI）的病理生理机制与巨噬细胞密切相关。在急性炎症期，M1型巨噬细胞通过激活NF‑κB信号通路，产生高水平细胞内ROS，在清除病原体的同时引发组织损伤^{［57‑58］}。进入增殖期后，巨噬细胞发生由M1型向M2型的极化转变。至纤维化期（或修复期），M2型巨噬细胞主导组织修复和纤维化过程^{［59‑60］}。研究^［61］表明，早期巨噬细胞发生M2极化可以降低ALI/ARDS死亡率和改善预后。大黄酸是多种中药（包括大黄、芦荟和番泻叶）的成分之一，具有较强的抗炎、抗肿瘤、抗纤维化、抗氧化等作用^{［62‑63］}。研究^［41］发现，大黄酸可通过激活TREM‑2上游转录因子NFATc1并与之相互作用，促进TREM‑2的表达，进而抑制NF‑κB的易位和活化，最终抑制巨噬细胞的M1极化，减轻ALI/ARDS后的肺部炎症。

REM‑2维持器官代谢稳态作用示意图见图2。

4 小结与展望

本综述系统阐述了TREM‑2在脓毒症复杂病理过程中的多重调控作用。现有研究表明，TREM‑2通过促进病原体清除^［8］、抑制过度炎症^［26］、协调组织修复^{［23‑24］}、桥接适应性免疫^［36］以及维持多器官功能稳态^{［37‑41］}等多重途径，在脓毒症中发挥着重要的保护作用。从分子机制来看，TREM‑2/DAP12信号轴及其下游的SYK、PI3K/AKT、ERK等通路构成其功能执行的核心基础^{［11‑12］}，而其可溶形式sTREM‑2则作为重要的调节分子和生物标志物^{［16‑17］}，进一步丰富了TREM‑2的调控网络。

然而，这一领域仍存在亟待解决的关键问题：尽管大量证据支持TREM‑2的积极作用，但最新研究发现其功能可能具有条件依赖性，甚至在某些情况下产生有害效应。例如，一项研究^［64］发现TREM2缺失反而可以提高脓毒症小鼠的存活率，减轻炎症和器官损伤。该研究发现TREM‑2能够直接结合磷酸酶SHP‑1的PTPase结构域，促使SHP‑1募集并抑制Bruton酪氨酸激酶（Bruton's tyrosine kinase，BTK）的磷酸化，从而阻断脂肪酸氧化（fatty acid oxidation，FAO）反应，导致促炎细胞因子释放增加和炎症介导的器官损伤加剧^［64］。这看似矛盾的结果提示，TREM‑2在脓毒症中的最终效应可能并非单一方向，而是受到病原体类型、感染阶段、细胞类型及组织微环境等多因素精细调控。例如，在感染早期或特定病原体作用下，TREM‑2可能主要发挥清除病原体和启动保护性免疫的作用；而在持续或过度炎症状态下，其信号可能通过某些通路（如上述SHP‑1/BTK/FAO轴）间接促进炎症损伤。因此，更加深入地阐明TREM‑2精准调控脓毒症的机制将成为未来研究的重点方向。

基于TREM‑2在免疫调节与器官保护中的作用，靶向TREM‑2无疑为脓毒症治疗提供了极具潜力的新策略。未来的研究应当深入解析其双向调节机制，明确其在各类免疫细胞及实质细胞中的特异性功能，并积极推动靶向治疗的转化研究，通过开发针对脓毒症的TREM‑2特异性调节剂，实现对脓毒症的精准治疗，为应对这一全球健康挑战开辟新的途径。

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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)