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摘要:
脂质运载蛋白2(lipocalin-2, LCN2)是人脂质运载蛋白家族的一员，已被证明与糖尿病、心血管疾病、肾脏疾病存在密切关联。近年来研究表明，LCN2通过介导炎症、氧化应激反应、铁死亡等路径在多种神经系统疾病的发生发展中发挥重要调节作用。本文从脑血管疾病、认知障碍性疾病、帕金森病、抑郁症及焦虑症等方面，阐述LCN2在神经系统疾病中作用机制，以期加深临床的认知。
Abstract:Lipocalin-2 (LCN2), a member of the human lipocalin family, has been demonstrated to be closely associated with diabetes, cardiovascular diseases, and renal disorders. Recent studies have indicated that LCN2 plays a significant regulatory role in the pathogenesis and progression of various neurological diseases by mediating pathways such as inflammation, oxidative stress, and ferroptosis. This article reviews the research advancements on the mechanism of LCN2 in neurological disorders, including cerebrovascular diseases, cognitive impairment disorders, Parkinson's disease, depression, and anxiety disorders, aiming to enhance clinical understanding.
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神经系统疾病具有发病率、致残率、致死率均高的特点，其发病机制复杂，涉及免疫、炎症反应、糖脂代谢异常、细胞坏死与凋亡等多个方面[1]。脂质运载蛋白2(lipocalin-2, LCN2)是一种新型脂肪细胞因子，广泛表达于中性粒细胞颗粒、巨噬细胞、上皮细胞、嗜酸性粒细胞和嗜碱性粒细胞[2]，具有调节免疫反应、维持铁稳态和促进上皮细胞分化等多种生理作用，其功能失调与肥胖症、代谢综合征和心血管疾病等多种疾病有关[3-4]。近年来研究发现，LCN2通过促进神经炎症和氧化应激、诱导铁死亡、降低突触可塑性等多种病理机制，在神经系统疾病的发生发展中发挥重要作用[5]。目前认为，LCN2在脑血管疾病、阿尔茨海默病(Alzheimer's disease, AD)、血管性痴呆(vascular dementia, VD)、帕金森病(Parkinson's disease, PD)、焦虑症(anxiety disorders)、抑郁症(depression)、脊髓损伤(spinal cord injuries, SCI)、肌萎缩侧索硬化(amyotrophic lateral sclerosis, ALS) 及多发性硬化(multiple sclerosis, MS)等多种神经系统疾病中表达异常，并可能与病情进展相关，成为神经系统疾病领域的新兴研究热点。本文总结LCN2在上述神经系统疾病发生发展中的作用机制，以期为展开相关疾病的病因学研究提供线索，并为遴选治疗靶点提供借鉴。
1. LCN2概述
LCN2是脂蛋白超家族的2号成员，基因定位于9号染色体9q34.11，相对分子质量为25 000，含197个氨基酸残基。成熟的LCN2由N端310螺旋、C端α螺旋和位于中间的8段反平行式β-折叠构成，可运输小分子和疏水分子，如类固醇、脂肪酸、维甲酸、前列腺素和性激素等[3-4]，24p3R为其最重要的受体[6]。乳腺、肺、胃肠、前列腺、中性粒细胞、脂肪细胞、星形胶质细胞等多种器官及细胞均可分泌LCN2[2]。在中枢神经系统中，LCN2主要由活化的星形胶质细胞所分泌，并通过自分泌或旁分泌方式与其受体24p3R结合发挥生理功能[7]。核因子κB(nuclear factor kappa B, NF-κB)信号通路、铁死亡通路、环鸟嘌呤-腺嘌呤核苷酸合成酶(cyclic GMP-AMP synthase, cGAS)-干扰素基因刺激蛋白(stimulator of interferon genes, STING)-转录因子阴阳1(YinYang 1, YY1)通路、迷走神经-肝脏-大脑皮层回路、LCN2/趋化因子配体10(lipocalin-2/C-X-C motif chemokine ligand 10, LCN2/CXCL10)信号通路及高迁移率族蛋白B1/核苷酸结合寡聚化结构域样受体蛋白3/细胞凋亡相关斑点样蛋白/半胱氨酸天冬氨酸特异性蛋白酶-1(high mobility group box 1/nod-like receptor protein 3/apoptosis-associated speck-like protein containing a CARD/cysteine aspartate-specific protease-1, HMGB1/NLRP3/PYCARD/caspase-1)等多个信号通路的激活可上调LCN2表达，而Janus激酶2/信号转导与转录激活子3(Janus kinase 2/signal transducer and activator of transcription 3, JAK2/STAT3)信号通路激活则可下调LCN2表达(表 1)。
表 1 LCN2在神经系统疾病中的主要信号传导通路及机制Table 1. The main signaling pathways and mechanisms of LCN2 in nervous system diseases序号 信号传导通路 机制 1 NF-κB信号通路 脑组织缺血缺氧后释放的炎症因子激活NF-κB信号通路，导致LCN2表达上调，加重神经炎症[8] 2 铁死亡通路 铁代谢紊乱可激活铁死亡通路，导致细胞内Fe2+浓度升高，促进LCN2表达，加剧神经损伤[9] 3 cGAS-STING-YY1通路 细胞在衰老过程中，小胶质细胞线粒体受损释放线粒体DNA，激活cGAS-STING-YY1轴，上调LCN2表达，促进星形胶质细胞衰老[10] 4 迷走神经-肝脏-大脑皮层回路 慢性压力可激活DMX脑区神经元，促进肝脏产生LCN2，与表达在mPFC脑区的LCN2受体结合，扰乱神经元活性，引起焦虑样行为[11] 5 LCN2/CXCL10信号通路 慢性应激状态可促进小胶质细胞极化，由M2型转变为M1型，并释放LCN2，激活LCN2/CXCL10信号通路，上调CXCL10表达，引起抑郁样行为[12] 6 HMGB1/NLRP3/PYCARD/caspase-1信号通路 脊髓损伤后炎症因子释放、活性氧增加，激活HMGB1/NLRP3/PYCARD/caspase-1信号通路，上调LCN2表达，加剧炎症反应和神经损伤[13] 7 JAK2/STAT3信号通路 活性氧及炎症因子激活JAK2/STAT3信号通路，下调LCN2表达，抑制星形胶质细胞增生和神经炎症[14-17] LCN2(lipocalin-2): 脂质运载蛋白2；NF-κB(nuclear factor kappa B)：核因子κB；cGAS(cyclic GMP-AMP synthase)：环鸟嘌呤-腺嘌呤核苷酸合成酶；STING(stimulator of interferon genes)：干扰素基因刺激蛋白；YY1(Yin-Yang 1)：转录因子阴阳1；DMX(dorsal motor vagal nucleus)：迷走神经运动核；mPFC(medial prefrontal cortex)：内侧前额叶皮质；CXCL10(C-X-C motif chemokine ligand 10)：趋化因子配体10；HMGB1(high mobility group box 1)：高迁移率族蛋白B1；NLRP3(nod-like receptor protein 3)：核苷酸结合寡聚化结构域样受体蛋白3；PYCARD(apoptosis-associated speck-like protein containing a CARD)：细胞凋亡相关斑点样蛋白；JAK2/STAT3(Janus kinase 2/signal transducer and activator of transcription 3)：Janus激酶2/信号转导与转录激活子3 2. LCN2与脑血管疾病
2.1 脑卒中
脑血管疾病是一个多因素作用、多机制参与的病理过程，涉及氧化应激、神经炎症、血脑屏障(blood-brain barrier, BBB)被破坏及神经元凋亡与坏死等多个环节。Xie等[18]在一项前瞻性研究中发现，急性缺血性脑卒中(acute ischemic stroke, AIS) 患者血清LCN2水平显著升高，且与美国国立卫生研究院卒中量表(National Institute of Health Stroke Scale, NIHSS)评分、90 d预后不良及早期神经功能恶化风险增加相关，提示LCN2有望成为评估脑卒中预后的潜在生物学标志物。
动物实验发现，LCN2及其受体在大脑中动脉闭塞(middle cerebral artery occlusion, MCAO)小鼠模型中表达上调，其中以在内皮细胞、中性粒细胞及在海马星形胶质细胞中的表达尤为显著[19]。Zhang等[14]发现，将人星形胶质细胞暴露在氧糖剥夺(oxygen glucose deprivation, OGD)环境中后，人星形胶质细胞增生与STAT3和JAK2磷酸化及LCN2表达水平上调相关，抑制LCN2-JAK2/STAT3信号通路表达可减少星形胶质细胞增生并减轻神经炎症。诱生型一氧化氮合酶(inducible nitric oxide synthase, INOS)是巨噬细胞经典活化M1型的标志物，脑卒中6 h后LCN2基因敲除小鼠的星形胶质细胞中未见INOS mRNA显著表达，提示LCN2在星形胶质细胞的激活中发挥关键调节作用[20]。Wan等[21]在MCAO小鼠模型中发现，LCN2表达增加可影响星形胶质细胞的吞噬功能，LCN2通过与低密度脂蛋白受体相关蛋白1(low density lipoprotein receptor, LRP1)相互作用可增强星形胶质细胞的吞噬作用，加剧脱髓鞘并导致神经功能进一步损伤。此外，脑卒中后中性粒细胞中LCN2表达水平亦会显著增加，并通过促进细胞内亚铁离子沉积，引起脂质过氧化物异常累积，从而进一步加重缺血性脑卒中程度[22]，上述研究表明LCN2高表达可能通过促进铁死亡，从而加剧缺血/再灌注损伤[23]。近期研究发现，LCN2可促进内皮细胞铁死亡，从而加重静脉溶栓后BBB功能障碍，抑制LCN2基因表达可显著降低AIS小鼠模型中枢神经系统中的铁死亡水平，而LCN2基因敲除小鼠脑卒中24 h时梗死体积减小，神经认知功能有所改善，提示抑制LCN2表达对脑卒中小鼠的神经功能具有保护作用[24-25]。
2.2 脑出血
Chen等[26]研究发现，与健康对照组相比，脑出血(cerebral hemorrhage, ICH)患者的血清LCN2水平显著升高，且与血清C反应蛋白、血糖、NIHSS评分、ICH评分及ICH体积呈正相关，与格拉斯哥昏迷量表(Glasgow coma scale，GCS)评分呈负相关，提示血清LCN2高水平表达是ICH预后不良的危险因素。最新研究发现，ICH小鼠脑组织小胶质细胞及星形胶质细胞中LCN2表达显著上调并参与小胶质细胞铁死亡过程[27]。进一步研究发现，由于LCN2仅抑制小胶质细胞中铁蛋白轻链水平，而对铁蛋白重链表达无影响，因此推测LCN2抑制铁蛋白轻链表达可能是其导致小胶质细胞铁死亡并诱导神经损伤的关键机制[9]。Yu等[28]研究发现，蛛网膜下腔出血(subarachnoid hemorrhage, SAH)患者脑脊液(cerebro spinal fluid, CSF)中LCN2水平较健康对照人群显著升高，且出血后第3天、第5天CSF LCN2水平对患者3个月预后不良具有一定提示作用。有研究发现，LCN2上调时常出现SAH后白质高信号，而LCN2基因敲除小鼠中无此种现象，并出现BBB损伤减轻，提示LCN2可能参与SAH后白质病理变化及BBB的破坏[29]。此外，在SAH小鼠模型中，大脑T2加权像中阳性血管数量显著高于假手术组，且LCN2基因敲除小鼠T2加权像中阳性血管数量较少，提示LCN2可能是SAH后超早期血栓形成的危险因素[30]。
上述研究表明，LCN2高表达可加重脑卒中、ICH等脑血管疾病神经损伤，并对患者预后产生不良影响，但也有少数研究得出相反结果。有研究者发现，AIS大鼠脑组织中LCN2表达上调有助于恢复神经元突触的可塑性，并促进抗炎因子白细胞介素-10(interleukin-10, IL-10)释放，从而减轻炎症损伤[31]。Du等[32]研究表明，LCN2在肿瘤坏死因子-α(tumor necrosis factor-α, TNF-α)诱导的脑损伤模型中可显著促进紧密连接蛋白表达，从而维持BBB完整性。LCN2在神经系统中发挥的双重作用可能与活化后激活不同下游通路有关。目前LCN2在脑血管疾病中发挥保护作用的相关研究较少，未来研究中需进一步明确LCN2作用的具体分子机制，并精准调控其表达，从而减轻脑血管疾病患者神经损伤，改善临床预后。
3. LCN2与认知障碍性疾病
3.1 阿尔茨海默病
AD是神经退行性疾病中最常见的类型，临床表现为进行性认知障碍和行为损害，病理特征包括脑内β-淀粉样蛋白(amyloid β-protein，Aβ)沉积增多、tau蛋白过度磷酸化及神经炎症。Hamad等[33]在一项横断面研究中发现，AD患者血清LCN2水平较健康对照人群显著升高。临床前期AD患者CSF Aβ42水平降低是AD的重要病理学特征，Eruysal等[34]发现与健康人群相比，临床前期AD患者的血浆LCN2水平显著升高，且与CSF中Aβ42水平呈负相关，提示血浆LCN2可能参与了AD的早期发病过程，并有望成为Aβ病理变化的早期血液学标志物。但也有研究发现，与健康对照人群相比，AD患者血浆LCN2显著下调，而且与非快速进展期AD患者相比，快速进展期AD患者LCN2水平更低[35-36]。上述研究表明，不同研究之间LCN2在AD患者中表达具有差异性，这可能与LCN2在AD的不同阶段具有复杂的作用机制相关。动物实验证实，AD小鼠反应性星形胶质细胞释放的LCN2显著增加，并可影响突触形态并降低树突棘密度，提示LCN2在反应性星形胶质细胞的突触毒性作用中发挥关键作用[37]。此外，有研究发现Aβ可诱导星形胶质细胞分泌LCN2，而铁螯合剂可抑制LCN2表达、减轻铁沉积，提示铁螯合剂的神经保护作用可能与抑制LCN2水平相关[38-39]。综上所述，Aβ诱导的胶质细胞激活和随后释放的LCN2可能参与AD神经炎性反应、突触毒性效应及铁沉积，从而加重AD病情。
3.2 血管性痴呆
VD是继AD之后第二常见的痴呆类型。Llorens等[40]在临床研究中证实，VD患者的CSF中LCN2水平均显著高于AD患者、其他神经退行性疾病患者及认知未受损的脑血管病患者，进一步分析发现，LCN2区分AD和VD的灵敏度为82%，特异度为87%，且不受VD和AD共存的影响，提示CSF LCN2有望成为潜在的VD诊断及鉴别诊断分子标志物。Meta分析得到了一致结论，研究者发现VD组CSF LCN2水平显著高于正常对照组，而血浆LCN2水平在两组之间无明显差异[41]。动物试验表明，抑制脑组织中LCN2表达有助于保护脑血管、维持BBB完整性，进而改善认知功能[42]。目前，LCN2在VD发病中的具体作用机制尚不明确，可能与诱导海马区神经元死亡[43]、抑制血管内皮生长因子-A(vascular endo-thelial growth factor-A, VEGF-A)表达[44]、促进神经炎症等多种病理机制有关，特异性干扰CSF中LCN2表达有望成为VD治疗的新策略。
4. LCN2与帕金森病
PD是一种常见的进行性神经退行性疾病。病例对照研究发现，PD患者血浆LCN2水平显著高于健康对照人群，且LCN2表达水平与PD患者认知功能、脑灰质体积、脑灰质体积与颅内总体积(脑灰质体积+脑白质体积+脑脊液体积)之比呈负相关[45]，与双侧黑质铁沉积水平呈正相关，提示LCN2可能通过调节铁代谢及神经炎症参与PD发病。研究表明，活化的小胶质细胞和星形胶质细胞介导的神经炎症在PD进展中起着重要作用[46]，而星形胶质细胞中的cGAS是诱导星形胶质细胞衰老和神经退行性变化的重要因子。研究发现LCN2是cGAS-STING信号通路的下游效应分子，cGAS-STING可通过诱导LCN2表达而促进星形胶质细胞衰老，进而加快PD进展[10]。但也有研究发现，与健康对照人群相比，PD患者血清LCN2水平无显著增加，且LCN2水平与统一帕金森病评分量表第三部分(unified Parkinson's disease rating scale-Ⅲ, UPDRS-Ⅲ)评分、蒙特利尔认知评估(Montreal cognitive assessment, MoCA)评分均无相关性[47]。上述研究提示LCN2在PD中具有复杂的潜在作用机制，可能涉及神经炎症及铁代谢调节等多方面，未来仍需进行更全面的研究，以阐明LCN2的功能。
5. LCN2与抑郁症及焦虑症
焦虑症及抑郁症是临床常见疾病。卒中后抑郁(post-stroke depression, PSD)是卒中的常见并发症之一[48]。Liu等[49]研究发现，入院时血清LCN2水平较高的AIS患者在出院时发生PSD的风险显著升高，即使调整混杂因素后血清高LCN2仍是PSD发生的独立危险因素。动物实验发现，炎症性肠病小鼠模型的脑组织中LCN2表达上调，并伴有抑郁样行为，而敲除LCN2基因可减轻此症状，表明LCN2参与调节炎症性肠病小鼠模型抑郁症状的发生[50]。
Yan等[43]研究发现，在焦虑障碍患者和慢性束缚应激(chronic restraint stress, CRS)小鼠模型中血清LCN2水平均显著升高，进一步研究发现慢性压力可激活走神经运动核(dorsal motor vagal nucleus, DMX)至肝脏的神经调节途径，以促进肝脏合成LCN2，继而通过破坏在内侧前额叶皮质(medial prefrontal cortex, mPFC)的神经元活动引发焦虑样行为。与之类似，有研究者发现，在慢性应激条件下，野生型小鼠海马区的细胞增殖显著减少，并表现出焦虑样行为和记忆损伤，而LCN2基因敲除小鼠的海马区细胞增殖未发生显著变化，小鼠亦未表现出焦虑样行为和记忆损伤[51]。上述研究表明，在慢性压力条件下，LCN2可抑制大脑的神经可塑性，进而引发焦虑样行为，提示LCN2在神经发生和焦虑症的病理生理过程中扮演着重要角色，但目前相关研究较少，详细作用机制和具体信号通路需进一步探究。
6. LCN2与神经系统其他疾病
LCN2表达水平在SCI、ALS、MS及慢性疼痛等多种神经系统疾病中均呈上调状态。Behrens等[52]通过制备动物模型发现，SCI小鼠脊髓、大脑、肝脏和血清中LCN2表达水平均显著增加，而在LCN2基因敲除SCI小鼠中星形胶质细胞增生标志物减少，表明LCN2可促进SCI中的星形胶质细胞增生。Müller等[13]最新研究发现，野生型小鼠在SCI后7 d出现高HMGB1/NLRP3/PYCARD/caspase-1炎症轴显著激活，并伴LCN2表达增多，敲除小鼠LCN2基因后上述炎症通路显著下调，SCI小鼠的运动功能得到改善。以上研究结果提示，LCN2可加重SCI导致的神经炎症，而降低LCN2表达水平有助于减轻神经炎症，从而改善SCI临床预后。
ALS是一种导致皮层、脑干和脊髓运动神经元进行性退化的神经肌肉疾病。Petrozziello等[53]研究发现，与健康对照组相比，ALS患者CSF和血液LCN2水平均显著升高，上调的LCN2通过促进神经炎症和神经元死亡，进而导致运动神经元发生进行性退化。慢性疼痛呈持续性，常引发情绪障碍和认知功能障碍，影响生活质量[54]。近期研究发现，由神经损伤引起慢性疼痛的小鼠模型中，前扣带皮层(anterior cingulate cortex, ACC)LCN2表达水平升高，使用特异性抗体中和LCN2可显著减轻疼痛程度，推测LCN2可导致ACC区域的谷氨酸能神经元过度激活，从而引起痛觉敏化[55]。这一发现为探索慢性疼痛的分子和细胞机制提供了线索，LCN2有望成为治疗慢性疼痛的潜在靶点。
MS是一种慢性中枢神经系统疾病，主要发病机制是免疫系统攻击神经纤维的髓鞘，进而导致脱髓鞘、炎症和神经损伤。Sciarretta等[56]在MS小鼠模型中发现，LCN2可促进促炎巨噬细胞表达，继而导致小鼠脊髓中炎症细胞浸润增和神经炎症加重。在LCN2基因敲除的MS小鼠模型中，脑组织炎症反应降低，脱髓鞘现象显著减少，提示LCN2可能是MS发生发展的促进因素[57]。但有研究者持不同观点，与野生型小鼠相比，LCN2基因敲除的MS小鼠少突胶质细胞损伤增加，炎症反应增强，认为LCN2可抑制少突胶质细胞损伤，在MS发生中具有潜在的保护作用[58]。因此，LCN2在MS中的作用尚存争议，需开展更多研究加以验证。
7. 小结与展望
LCN2是一种重要的炎症介质，同时也是铁蛋白转运的重要调节因子，在神经炎症、脂质运输、铁蛋白转运等多方面发挥关键作用。本文总结了LCN2在脑血管疾病、认知障碍性疾病、帕金森病等神经系统疾病发生发展中作用的研究进展，有助于临床工作者及时全面了解LCN2研究动态和热点，从而为神经系统疾病的诊治提供更多线索，但由于LCN2在各类神经系统疾病中的表达水平变化不一致，甚至在同一疾病中表现出截然相反的作用，因此未来需进一步阐明LCN2的具体作用机制，从而更好地指导临床诊疗。
作者贡献：周永泰、杨朕钰负责查阅文献、论文撰写；李岩、吴嘉静负责修订论文；赵波负责选题设计和论文审校。利益冲突：所有作者均声明不存在利益冲突 -
表 1 LCN2在神经系统疾病中的主要信号传导通路及机制
Table 1 The main signaling pathways and mechanisms of LCN2 in nervous system diseases
序号 信号传导通路 机制 1 NF-κB信号通路 脑组织缺血缺氧后释放的炎症因子激活NF-κB信号通路，导致LCN2表达上调，加重神经炎症[8] 2 铁死亡通路 铁代谢紊乱可激活铁死亡通路，导致细胞内Fe2+浓度升高，促进LCN2表达，加剧神经损伤[9] 3 cGAS-STING-YY1通路 细胞在衰老过程中，小胶质细胞线粒体受损释放线粒体DNA，激活cGAS-STING-YY1轴，上调LCN2表达，促进星形胶质细胞衰老[10] 4 迷走神经-肝脏-大脑皮层回路 慢性压力可激活DMX脑区神经元，促进肝脏产生LCN2，与表达在mPFC脑区的LCN2受体结合，扰乱神经元活性，引起焦虑样行为[11] 5 LCN2/CXCL10信号通路 慢性应激状态可促进小胶质细胞极化，由M2型转变为M1型，并释放LCN2，激活LCN2/CXCL10信号通路，上调CXCL10表达，引起抑郁样行为[12] 6 HMGB1/NLRP3/PYCARD/caspase-1信号通路 脊髓损伤后炎症因子释放、活性氧增加，激活HMGB1/NLRP3/PYCARD/caspase-1信号通路，上调LCN2表达，加剧炎症反应和神经损伤[13] 7 JAK2/STAT3信号通路 活性氧及炎症因子激活JAK2/STAT3信号通路，下调LCN2表达，抑制星形胶质细胞增生和神经炎症[14-17] LCN2(lipocalin-2): 脂质运载蛋白2；NF-κB(nuclear factor kappa B)：核因子κB；cGAS(cyclic GMP-AMP synthase)：环鸟嘌呤-腺嘌呤核苷酸合成酶；STING(stimulator of interferon genes)：干扰素基因刺激蛋白；YY1(Yin-Yang 1)：转录因子阴阳1；DMX(dorsal motor vagal nucleus)：迷走神经运动核；mPFC(medial prefrontal cortex)：内侧前额叶皮质；CXCL10(C-X-C motif chemokine ligand 10)：趋化因子配体10；HMGB1(high mobility group box 1)：高迁移率族蛋白B1；NLRP3(nod-like receptor protein 3)：核苷酸结合寡聚化结构域样受体蛋白3；PYCARD(apoptosis-associated speck-like protein containing a CARD)：细胞凋亡相关斑点样蛋白；JAK2/STAT3(Janus kinase 2/signal transducer and activator of transcription 3)：Janus激酶2/信号转导与转录激活子3 
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