cGAS-STING信号通路在儿童免疫介导炎症性疾病中的研究进展

Research progress on the cGAS-STING signaling pathway in immune-mediated inflammatory diseases in children

摘要

环鸟苷酸-腺苷酸合成酶（cyclic GMP-AMP synthase, cGAS）-干扰素基因刺激因子（stimulator of interferon gene, STING）信号通路是免疫系统的重要组成部分，其通过识别细胞质中异常双链DNA，促进Ⅰ型干扰素等炎症因子表达，保护机体免受病原体感染。儿童免疫系统发育未成熟或存在基因突变时，易出现免疫紊乱，增加自身免疫性疾病（autoimmune disease, AID）和自身炎症性疾病的发病风险。近年研究表明，cGASSTING信号通路异常激活与儿童AID和自身炎症性疾病发生相关。该文对cGAS-STING信号通路在儿童AID及自身炎症性疾病中的研究进展进行综述，以期为临床诊疗提供新方向。[中国当代儿科杂志，2025,27 (7):881-886，Ⅴ]

Abstract

The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon gene (STING) signaling pathway is a crucial component of the immune system. It detects abnormal cytosolic double-stranded DNA and promotes the expression of type I interferons and other inflammatory factors, thereby protecting the body from pathogenic infections. In children, an immature immune system or genetic mutations can lead to immune dysregulation, increasing the risk of autoimmune diseases (AID) and autoinflammatory diseases. Recent studies have shown that aberrant activation of the cGAS-STING signaling pathway is associated with the development of AID and autoinflammatory diseases in children. This review summarizes the research progress on the cGAS-STING signaling pathway in childhood AID and autoinflammatory diseases, aiming to provide new directions for clinical diagnosis and treatment.

关键词

环化鸟苷酸-腺苷酸合成酶 / 干扰素基因刺激因子 / 信号通路 / 自身免疫性疾病 / 自身炎症性疾病 / 儿童

Key words

Cyclic GMP-AMP synthase / Stimulator of interferon gene / Signaling pathway / Autoimmune disease / autoinflammatory diseases / Child

儿童自身免疫性疾病（autoimmune disease, AID）是由于机体免疫功能处于异常状态，免疫系统识别自身抗原，伴有体内多种自身抗体产生，引起细胞破坏、组织及器官损伤，出现一系列临床症状的炎症性疾病^［1］。儿童自身炎症性疾病是由于免疫基因发生突变，其编码蛋白也随之发生改变，造成免疫缺陷或失调而引起全身炎症反应的一类疾病^［2］。

环鸟苷酸-腺苷酸合成酶（cyclic GMP-AMP synthase, cGAS）-干扰素基因刺激因子（stimulator of interferon gene, STING）信号通路是免疫系统的重要组成部分，当有病原体入侵时，病原体异常双链DNA（double-stranded DNA, dsDNA）与cGAS结合，激活机体的免疫应答，保护机体免受病原体入侵^［3］。除病原体dsDNA外，自身dsDNA也能激活cGAS-STING通路。在生理情况下，细胞中的dsDNA大多被限制在细胞核或线粒体中^［4］。当细胞损伤时，胞质中异常积累的dsDNA可持续激活cGAS-STING信号通路，引发攻击自身的炎症反应，进而参与AID的发生发展^［5］。编码cGAS或STING蛋白的基因发生突变，可导致固有免疫失调并引发持续炎症反应，这是自身炎症性疾病发生的重要机制^［2］。

本文对cGAS-STING信号通路在儿童AID和自身炎症性疾病中的作用机制进行综述，以期为临床治疗儿童AID和自身炎症性疾病提供更多思路。

1 cGAS-STING信号通路的组成和信号传递

cGAS-STING通路由识别dsDNA的cGAS、位于内质网上的STING和下游信号分子组成，其信号传递分为dsDNA识别、cGAMP与STING结合以及免疫应答激活3个部分。

1.1　cGAS识别并结合dsDNA

在生理情况下，细胞内的dsDNA多位于细胞核或线粒体中，细胞质中几乎不会有dsDNA存在^［6］。细胞中存在多种降解dsDNA的酶，其中3-修复外切酶（three-prime repair exonuclease, TREX1）是一种核酸外切酶，可清除胞质中的dsDNA，从而避免自身免疫反应的发生，当该酶缺失或活性降低时，dsDNA会在胞质中异常积累^［7］。脱氧核糖核酸酶Ⅱ（deoxyribonuclease Ⅱ, DNase Ⅱ）是位于溶酶体中的核酸内切酶，可参与清除dsDNA。有研究发现，DNase Ⅱ缺失小鼠出生时死亡，而同时敲除cGAS或STING基因的DNase Ⅱ缺失小鼠则可正常发育，且体内抗dsDNA抗体水平明显下降^［8］。

cGAS是一种核酸转移酶（约60 kDa），由522个氨基酸组成^［9］。cGAS的N端结构域通过促进cGAS二聚化并结合磷酸肌苷，C端包含核苷酸转移酶结构域和Mab21结构域，核苷酸转移酶结构域在调节cGAS酶活性方面扮演重要角色^［10］。Mab21结构域中存在的锌指结构使cGAS具有特异性，能高效地识别dsDNA，抑制该结构域将导致cGAS无法识别dsDNA^［11］。cGAS通过与脱氧核糖磷酸骨架结合来识别dsDNA，结合无序列特异性但具有长度特异性，即结合的长度需要超过45个核苷酸，由此cGAS几乎能够识别所有类型的dsDNA和部分单链DNA^［12］。cGAS不与dsDNA结合时，处于静止状态，当病原体dsDNA进入细胞或自身dsDNA异常积累，这些dsDNA被机体胞质dsDNA感受器cGAS识别^［13］。dsDNA结合cGAS使其构象变化从而活化cGAS，后者与dsDNA结合形成2cGAS-2dsDNA复合物^［14］。cGAS形成活性二聚体结构，催化胞内三磷酸腺苷（adenosine triphosphate, ATP）和三磷酸鸟苷（guanosine triphosphate, GTP）生成环磷酸鸟苷-磷酸腺苷（cyclic-GMP-AMP, cGAMP）^［15］。

1.2　cGAMP与STING结合

cGAMP因其磷酸二酯键的位置也被称为2',3'-cGAMP，作为第二信使与STING结合^［16］。STING是位于内质网上的跨膜蛋白，其N-末端结构域包含4个跨膜蛋白，对STING起到锚定作用；其C-末端结构域包括配体结合结构域和C-末端尾巴结构域，后者存在与TBK1结合的结构域^［17］。正常状态下，STING以二聚体形式与内质网结合，其C端结构域形成配体结合口袋，可特异性结合2',3'-cGAMP^［18］。当细胞内cGAMP浓度升高，cGAMP与STING结合使STING二聚体寡聚化并活化，活化后的STING通过内质网-高尔基体中间室，从内质网转运至高尔基体，激活下游免疫反应^［19］。此外，cGAMP在细胞间连接蛋白的作用下，能够激活邻近细胞中的STING，从而扩大炎症反应范围^［20］。

1.3　免疫应答激活

STING由内质网转入高尔基体，在Cys88和Cys91半胱氨酸残基作用下发生棕榈酰化，这一过程对STING的激活起到促进作用^［21］。活化的STING招募TBK1，进而招募干扰素调节因子3（interferon regulatory factor 3, IRF3），使其磷酸化，磷酸化的IRF3发生核转位，促进Ⅰ型干扰素（type Ⅰ interferon, IFN-Ⅰ）和干扰素刺激基因（interferon-stimulated gene, ISG）的表达^［22］。

NF-κB的抑制蛋白（inhibitor of NF-κB, IκB）与NF-κB结合，此时NF-κB处于静息状态^［23］。STING作为内质网上的跨膜蛋白，通过激活IKK激酶使IκB磷酸化随后被降解，NF-κB被激活后进入细胞核，促进IFN-Ⅰ和白细胞介素（interleukin, IL）-6、IL-1β以及肿瘤坏死因子-α（tumor necrosis factor-α, TNF-α）等炎症因子的表达，引起炎症反应^［24］。

2 cGAS-STING信号通路与疾病

儿童AID的发病机制复杂，被认为是遗传、环境等因素共同作用的结果，其特征是免疫系统过度活跃。IFN-Ⅰ可以促进机体多种免疫细胞的分化成熟，导致大量炎症因子及自身抗体的产生，在多种儿童AID发病机制中起关键作用。儿童自身炎症性疾病则是由先天免疫系统缺陷或失调引起的疾病，其特征是反复持续性炎症和缺乏适应性免疫。2022年国际免疫学会联合会根据病理生理学特征，将自身炎症性疾病分为3类：IFN-Ⅰ通路疾病、炎性小体缺陷和非炎性小体相关疾病^［25］。cGAS-STING信号通路是调控IFN-Ⅰ的重要信号通路之一，与儿童AID和自身炎症性疾病的发生发展密切相关。

2.1　cGAS-STING信号通路与儿童系统性红斑狼疮

儿童系统性红斑狼疮（childhood systemic lupus erythematosus, cSLE）占系统性红斑狼疮（systemic lupus erythematosus, SLE）病例的10%~20%^［26］。cSLE发病机制与成人SLE相似，临床症状同样具有多样性，但各器官受累风险更高^［27］，影响儿童的生理、心理健康^［28］。

胞质异常dsDNA积累是激活cGAS-STING信号通路的关键因素，SLE患者血清中dsDNA水平升高，通过cGAS-STING途径促进IFN-Ⅰ表达，激活免疫系统并介导组织器官损伤。受损组织释放的dsDNA进一步形成正反馈调节，导致干扰素持续产生并加重组织损伤^［29］。SLE患者血清中ISG、IFN-Ⅰ的表达水平显著高于健康人群，促进IFNs的表达激活免疫反应^［30］。SLE患者外周血单核细胞中cGAS表达显著高于健康人群^［31］。SLE小鼠模型的肾脏、卵巢、结肠等多脏器中cGAS、STING基因的表达水平均高于对照组，表明cGAS-STING信号通路参与SLE中多脏器的损伤过程^［32］。紫外线照射可诱发SLE的疾病活动，可能与诱导细胞DNA氧化损伤、激活cGAS-STING信号通路、导致过度免疫反应有关^［33］。

2.2　cGAS-STING信号通路与幼年特发性关节炎

幼年特发性关节炎（juvenile idiopathic arthritis, JIA）属于一种慢性、自身免疫性疾病，多见于16岁以下儿童^［34］。全身型幼年特发性关节炎（systemic juvenile idiopathic arthritis, sJIA）约占JIA病例总数的10%^［35］。sJIA患儿常表现为关节炎伴发热、皮疹、滑膜炎等全身症状，部分患儿合并多系统受累，影响儿童身心健康^［36］。

sJIA患者外周血中性粒细胞数量显著增加，当病原体被固有免疫细胞表面的Toll样受体识别后，诱导活性氧产生，从而引发线粒体损伤，导致线粒体DNA释放到胞质中^［37］。此外，sJIA患者体内中性粒细胞呈现过度活化状态，释放中性粒细胞胞外诱捕网，其中包括dsDNA、组蛋白等成分^［38］。这会引起细胞质内dsDNA积累，被cGAS识别后激活cGAS-STING信号通路，招募TBK1并磷酸化IRF3，后者进入细胞核，进一步诱导IFN-Ⅰ和促炎因子如TNF-α和IL-6的产生，最终引起炎症反应^［39］。在这些炎症因子中，IL-6是sJIA的核心介质，在sJIA患者外周血和滑膜液中有升高趋势^［40］。IL-6作用于肝脏可促进急性期蛋白合成，同时刺激破骨细胞增殖，临床表现为C反应蛋白升高、关节破坏及骨质疏松^［41］。

2.3　cGAS-STING信号通路与Aicardi-Goutières综合征

Aicardi-Goutières综合征（Aicardi-Goutières syndrome, AGS）是一种罕见的遗传性自身炎症性疾病，可累及全身多系统。患儿多在出生后1年内发病，病死率及致残率较高，仅少数患者可存活至30岁以上^［42］。临床表现为神经-皮肤-免疫综合征，具体表现为：神经系统可见小头畸形、智力障碍；皮肤呈现反复冻疮样损伤；伴随免疫功能紊乱，可能出现SLE、肿瘤易感性增加等^［43］。

AGS与基因突变相关，目前发现的致病基因有TREX1、RNASEH2B、RNASEH2C、RNASEH2A、SAMHD1、ADAR、IFIH1、LSM11和RNU7-1^［44］。TREX1基因与dsDNA分子降解有关，SAMHD1、RNASEH2A、RNASEH2B和RNASEH2C基因则影响DNA复制^［45］。上述基因发生基因突变时，细胞质内dsDNA或RNA过度累积，激活cGAS-STING信号通路，促进IFN-Ⅰ的分泌^［46］。TREX1基因缺陷小鼠胞质dsDNA过度积累，可出现类似人AGS综合征的疾病表现，而抑制cGAS或STING可减轻其炎症反应，降低病死率^［47］。

2.4　cGAS-STING信号通路与刺激蛋白相关干扰素基因血管病变

婴儿期发病的刺激蛋白相关干扰素基因血管病变是一种单基因遗传性自身炎症性疾病^［48］，该疾病可累及多脏器，通常表现为新生儿期全身炎症反应、皮疹、生长受限，后期可出现间质性肺病、肺动脉高压等严重并发症^［49］。

对患病儿童及其家系进行基因检测，发现编码STING的基因TMEM173存在显性突变（N154S、V155M和V147L）^［50］。没有dsDNA刺激的情况下，患儿体内的STING仍然处于持续激活状态，从而促使IFN-Ⅰ产生，进一步导致内皮细胞凋亡，并引发皮肤血管病变和肺部炎症。患儿外周血中检测到的高水平IFN-Ⅰ也验证了这一结论^［51］。

2.5　cGAS-STING信号通路与Wiskott-Aldrich综合征

Wiskott-Aldrich综合征（Wiskott-Aldrich syndrome, WAS），又称湿疹-血小板减少伴免疫缺陷综合征，是由WAS基因突变导致的先天性免疫缺陷性疾病^［52］。WAS基因位于X染色体上，其编码的Wiskott-Aldrich综合征蛋白（Wiskott-Aldrich syndrome protein, WASP）是重要的肌动蛋白细胞骨架调节剂，在维持细胞器形状和运输方面发挥关键作用^［53］。WASP可将T细胞受体信号转导至肌动蛋白聚合，促进T细胞与抗原提呈细胞的稳定接触；还可调控B细胞与滤泡辅助性T细胞的相互作用，影响生发中心形成。当WASP缺乏时，T细胞无法有效形成免疫突触，导致T细胞活化及增殖减少；同时，生发中心形成减少，B细胞与辅助性T细胞的稳定结合受损，影响B细胞成熟。综上，WASP缺乏可导致T细胞和B细胞功能异常，与免疫缺陷的发生相关^［54］。WAS还可出现溶血性贫血、血管炎和关节炎等自身免疫性炎症表现，WASP功能缺失与自身免疫表现之间的关系尚未明确。

WASP可减少dsDNA双链断裂（DNA double-strand break, DSB）的形成，参与DSB的修复，还可促进电离辐射导致的dsDNA损伤的修复，有维持基因组稳定的作用。当WASP缺失时，树突状细胞摄取的dsDNA无法正常降解，被释放到细胞质中，从而激活cGAS-STING信号通路^［55］。WASP也与溶酶体的成熟过程相关，其缺失会导致溶酶体成熟延迟，进而阻碍由自身dsDNA和自身抗体结合形成的免疫复合物转运，使自身dsDNA进入细胞质并激活cGAS-STING信号通路。cGAS-STING信号通路激活后，IFN-Ⅰ产生增加，最终引发炎症反应^［56］。

3 与cGAS-STING信号通路相关的药物

持续性激活cGAS-STING信号通路，是AID和自身炎症性疾病发生发展的重要机制，调控cGAS-STING信号通路对儿童AID和自身炎症性疾病的治疗具有重要意义。

3.1　cGAS抑制剂

cGAS作为胞质dsDNA传感器，与dsDNA结合后结构发生变化，这是cGAS-STING信号通路被激活的关键步骤。cGAS赖氨酸位点（Lys384、Lys394或Lys414）乙酰化可使其处于静止状态，当胞质出现dsDNA时，cGAS赖氨酸去乙酰化，cGAS处于激活状态^［57］。激活的cGAS利用ATP和GTP生成cGAMP，cGAMP作为第二信使，通过结合STING蛋白激活下游免疫反应^［8］。

抗疟药物（如羟氯喹）可作用于2cGAS-2dsDNA复合物的结合界面，通过抑制cGAS和dsDNA之间的相互作用来抑制cGAS激活，下调cGAS、STING蛋白表达，是AGS、SLE等疾病的治疗药物^［58］。有研究发现，阿司匹林通过乙酰化抑制cGAS激活，降低TREX1缺陷小鼠ISG、IFN-Ⅰ表达，从而减轻炎症反应，延长TREX1缺陷小鼠的生存期^［57］。

RU.521可以降低cGAS对ATP和GTP的亲和力，减少cGAMP产生，降低TREX1缺陷小鼠骨髓源性巨噬细胞（bone marrow derived macrophages, BMDM）中IFN-Ⅰ的表达水平，但是对人源性cGAS无明显效果^［59］。小分子G140和G150通过占据ATP和GTP结合活性位点来抑制其与人源性cGAS的结合^［60］。

3.2　STING抑制剂

STING的棕榈酰化对于其在高尔基体中的激活至关重要。硝基呋喃衍生物可有效抑制STING棕榈酰化，其中C-178和C-176对于小鼠STING具有特异性抑制作用，而H-151对人STING具有特异性抑制作用^［61］。病毒入侵机体时，内源性硝基脂肪酸通过共价修饰STING，抑制其棕榈酰化，导致STING信号通路失活，从而抑制AID中IFN-Ⅰ的产生^［62］。

除影响STING活性外，来源于紫菀的化合物Astin C还可通过竞争性结合STING，阻断IRF3的招募；compound 18与STING的亲和力高于cGAMP，通过竞争性结合STING抑制其下游信号通路，减少IFN-Ⅰ等炎症因子的释放^［63］。另有研究报道，名为Gelsevirine的生物碱可降解STING蛋白，减弱cGAS-STING信号通路激活，降低炎症因子水平，进而缓解STING通路介导的骨关节炎^［64］。

4 总结与展望

综上，cGAS-STING信号通路与多种儿童AID和自身炎症性疾病的发生密切相关。在正常生理状态下，该通路主要通过调节免疫反应发挥机体保护作用，而当通路异常激活时，则会促进疾病的发生发展。经过多年研究，在通过抑制cGAS-STING通路治疗AID和自身炎症性疾病领域已取得显著进展，针对cGAS和STING的抑制剂也展现出良好的前景，未来针对cGAS-STING信号通路相关免疫性疾病的靶向治疗仍需持续探索。

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