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Article(id=1190669169357112314, tenantId=1146029695717560320, journalId=1189873630562394117, issueId=1190669163988398295, articleNumber=null, orderNo=null, doi=10.11855/j.issn.0577-7402.1112.2024.0813, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=research-article, receivedDate=1692460800000, receivedDateStr=2023-08-20, revisedDate=null, revisedDateStr=null, acceptedDate=1711036800000, acceptedDateStr=2024-03-22, onlineDate=1761807251537, onlineDateStr=2025-10-30, pubDate=1745769600000, pubDateStr=2025-04-28, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1761807251537, onlineIssueDateStr=2025-10-30, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1761807251537, creator=13701087609, updateTime=1761807251537, updator=13701087609, issue=Issue{id=1190669163988398295, tenantId=1146029695717560320, journalId=1189873630562394117, year='2025', volume='50', issue='4', pageStart='367', pageEnd='503', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=0, createTime=1761807250258, creator=13701087609, updateTime=1761807667423, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1190670913772339410, tenantId=1146029695717560320, journalId=1189873630562394117, issueId=1190669163988398295, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1190670913772339411, tenantId=1146029695717560320, journalId=1189873630562394117, issueId=1190669163988398295, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=483, endPage=489, ext={EN=ArticleExt(id=1190669169633936381, articleId=1190669169357112314, tenantId=1146029695717560320, journalId=1189873630562394117, language=EN, title=Research progress of immunometabolic mechanism for GLP-1 to modulate T cell dysfunction in sepsis, columnId=1190243275882729994, journalTitle=Medical Journal of Chinese People’s Liberation Army, columnName=Review, runingTitle=null, highlight=null, articleAbstract=

Persistent inflammation, immuno-suppression and catabolism syndrome (PICS) occurs at the later stage of sepsis, characterized by T cell dysfunction with severe poor outcome. Recent studies found that T cell function be largely affected by its metabolic status. In sepsis, a variety of signaling molecules, including the nutrients, could trigger T cell to undergo metabolic reprogramming that from oxidative phosphorylation to aerobic glycolysis via phosphatidylinositol 3-kinase (PI3K)-serine/threonine kinases (Akt)-mammalian target of rapamycin (mTOR) pathway, leading to severe alterations of its immune phenotype. Glucagon-like peptide-1 (GLP-1) is a kind of incretin hormone that could regulate nutrients and energy metabolism in the body. It can reduce blood glucose level, suppress the immune and inflammatory responses. Plasma GLP-1 levels were rapidly elevated in sepsis and correlated closely with the outcome in critical care. GLP-1 receptor (GLP-1R) agonist could block the glycolysis of T cells, reduce glucose transporter type 1 mRNA expression, and inhibit T cell proliferation. Therefore, the elevated GLP-1 level may represent the metabolic switch toward "aerobic glycolysis", reflecting the pathological status of PICS. Here, the review elucidates the regulation of GLP-1 on the immune function and metabolic reprogramming of T cells and provides strategies for the prevention and treatment of T cell immune dysfunction in sepsis via GLP-1 receptor.

, correspAuthors=Qing-Hong Zhang, authorNote=null, correspAuthorsNote=
E-mail:
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脓毒症晚期发生持续性炎症反应、免疫抑制和分解代谢综合征(PICS)，而T淋巴细胞功能障碍是PICS的重要特征。T淋巴细胞的营养代谢状态严重影响其免疫功能。脓毒症时各种信号分子包括营养素，通过磷脂酰肌醇-3激酶(PI3K)-丝氨酸/苏氨酸激酶(Akt)-哺乳动物雷帕霉素靶蛋白(mTOR)信号通路促进T淋巴细胞发生代谢重编程，从而改变其免疫表型。胰高血糖素样肽-1(GLP-1)是一种调节物质和能量代谢的肠促胰素，具有降糖、免疫抑制和抗炎的作用，脓毒症时其水平急剧升高，并与危重患者的病情和预后密切相关。GLP-1受体(GLP-1R)激动剂可阻断T淋巴细胞的糖酵解，抑制葡萄糖转运蛋白mRNA的表达，从而抑制T淋巴细胞增殖。因此，脓毒症时内源性GLP-1水平升高可能代表机体能量代谢向有氧糖酵解转换，反映的是PICS的一种病理状态。本文阐述GLP-1对脓毒症T淋巴细胞免疫功能和代谢重编程的调控作用，以为通过GLP-1R防治脓毒症T淋巴细胞功能障碍提供策略参考。

, correspAuthors=张庆红, authorNote=null, correspAuthorsNote=
张庆红，E-mail：
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刘红升，博士研究生，副主任医师，主要从事脓毒症的肠道黏膜屏障损伤机制研究

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刘红升，博士研究生，副主任医师，主要从事脓毒症的肠道黏膜屏障损伤机制研究

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刘红升，博士研究生，副主任医师，主要从事脓毒症的肠道黏膜屏障损伤机制研究

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PICS. 持续性炎症反应、免疫抑制和分解代谢综合征

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GLP-1调控脓毒症T淋巴细胞功能障碍的免疫代谢机制研究进展
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刘红升 1 , 张庆红 2, *
解放军医学杂志 | 综述 2025,50(4): 483-489
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解放军医学杂志 | 综述 2025, 50(4): 483-489
GLP-1调控脓毒症T淋巴细胞功能障碍的免疫代谢机制研究进展
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刘红升1, 张庆红2, *
作者信息
  • 1解放军总医院第四医学中心急诊医学科，北京 100048
  • 2解放军总医院医学创新研究部创伤修复与组织再生研究中心，北京 100853

    • 刘红升，博士研究生，副主任医师，主要从事脓毒症的肠道黏膜屏障损伤机制研究

通讯作者:

张庆红，E-mail：
Research progress of immunometabolic mechanism for GLP-1 to modulate T cell dysfunction in sepsis
Hong-Sheng Liu1, Qing-Hong Zhang2, *
Affiliations
  • 1Department of Emergency, the Fourth Medical Center of Chinese PLA General Hospital, Beijing 100048, China
  • 2Trauma Repair and Tissue Regeneration Center, Department of Medical Innovation Study, Chinese PLA General Hospital, Beijing 100853, China
出版时间: 2025-04-28 doi: 10.11855/j.issn.0577-7402.1112.2024.0813
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脓毒症晚期发生持续性炎症反应、免疫抑制和分解代谢综合征(PICS)，而T淋巴细胞功能障碍是PICS的重要特征。T淋巴细胞的营养代谢状态严重影响其免疫功能。脓毒症时各种信号分子包括营养素，通过磷脂酰肌醇-3激酶(PI3K)-丝氨酸/苏氨酸激酶(Akt)-哺乳动物雷帕霉素靶蛋白(mTOR)信号通路促进T淋巴细胞发生代谢重编程，从而改变其免疫表型。胰高血糖素样肽-1(GLP-1)是一种调节物质和能量代谢的肠促胰素，具有降糖、免疫抑制和抗炎的作用，脓毒症时其水平急剧升高，并与危重患者的病情和预后密切相关。GLP-1受体(GLP-1R)激动剂可阻断T淋巴细胞的糖酵解，抑制葡萄糖转运蛋白mRNA的表达，从而抑制T淋巴细胞增殖。因此，脓毒症时内源性GLP-1水平升高可能代表机体能量代谢向有氧糖酵解转换，反映的是PICS的一种病理状态。本文阐述GLP-1对脓毒症T淋巴细胞免疫功能和代谢重编程的调控作用，以为通过GLP-1R防治脓毒症T淋巴细胞功能障碍提供策略参考。

胰高血糖素样肽-1  /  T淋巴细胞功能障碍  /  脓毒症  /  免疫代谢

Persistent inflammation, immuno-suppression and catabolism syndrome (PICS) occurs at the later stage of sepsis, characterized by T cell dysfunction with severe poor outcome. Recent studies found that T cell function be largely affected by its metabolic status. In sepsis, a variety of signaling molecules, including the nutrients, could trigger T cell to undergo metabolic reprogramming that from oxidative phosphorylation to aerobic glycolysis via phosphatidylinositol 3-kinase (PI3K)-serine/threonine kinases (Akt)-mammalian target of rapamycin (mTOR) pathway, leading to severe alterations of its immune phenotype. Glucagon-like peptide-1 (GLP-1) is a kind of incretin hormone that could regulate nutrients and energy metabolism in the body. It can reduce blood glucose level, suppress the immune and inflammatory responses. Plasma GLP-1 levels were rapidly elevated in sepsis and correlated closely with the outcome in critical care. GLP-1 receptor (GLP-1R) agonist could block the glycolysis of T cells, reduce glucose transporter type 1 mRNA expression, and inhibit T cell proliferation. Therefore, the elevated GLP-1 level may represent the metabolic switch toward "aerobic glycolysis", reflecting the pathological status of PICS. Here, the review elucidates the regulation of GLP-1 on the immune function and metabolic reprogramming of T cells and provides strategies for the prevention and treatment of T cell immune dysfunction in sepsis via GLP-1 receptor.

glucagon-like peptide-1  /  T cell dysfunction  /  sepsis  /  immunometabolism
刘红升, 张庆红. GLP-1调控脓毒症T淋巴细胞功能障碍的免疫代谢机制研究进展. 解放军医学杂志, 2025 , 50 (4) : 483 -489 . DOI: 10.11855/j.issn.0577-7402.1112.2024.0813
Hong-Sheng Liu, Qing-Hong Zhang. Research progress of immunometabolic mechanism for GLP-1 to modulate T cell dysfunction in sepsis[J]. Medical Journal of Chinese People’s Liberation Army, 2025 , 50 (4) : 483 -489 . DOI: 10.11855/j.issn.0577-7402.1112.2024.0813
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脓毒症晚期发生持续性炎症反应、免疫抑制和分解代谢综合征(persistent inflammation immuno-suppression and catabolism syndrome，PICS)，造成顽固性感染直至死亡[1]。PICS是慢性危重症(chronic critical illness，CCI；重症监护室ICU≥14 d伴多器官功能障碍)和长期预后不良的重要机制[2]。ICU出院后1年，PICS患者中50%死亡，25%卧床不起[3]。此外，老年患者(≥65岁)较年轻患者(18~64岁)PICS发病率高，各项指标严重恶化[4]。随着我国人口老龄化加剧，探索PICS发病机制、寻找新的治疗策略迫在眉睫。脓毒症神经内分泌调控一直是临床重要的治疗手段和研究热点。胰高血糖素样肽-1(glucagon-like peptide-1，GLP-1)是机体在进食、创伤和感染时分泌的一种肠促胰素，具有抗炎、抑制免疫和降糖的作用[5]，正好对应PICS三联征。脓毒症患者血浆GLP-1水平持续升高，并与感染和预后密切相关，提示内源性GLP-1水平的升高可能与脓毒症PICS的发生发展密切相关。T淋巴细胞功能障碍是脓毒症重要的病理特征，而T淋巴细胞的代谢状态严重影响其免疫功能。脓毒症时T淋巴细胞发生代谢重编程，即从氧化磷酸化转换为有氧糖酵解，从而从促炎表型向抗炎或免疫调节表型转化。除调控全身能量代谢外，GLP-1还可抑制T淋巴细胞的糖酵解[6]。由此推测，GLP-1可能通过影响T淋巴细胞的能量代谢，调控T淋巴细胞的免疫功能，从而影响PICS的进程。本文综述GLP-1调控烧伤脓毒症中T淋巴细胞免疫功能的能量代谢机制，分析PICS发生发展的内分泌调控机制，以期为通过GLP-1干预T淋巴细胞能量代谢而防治脓毒症提供策略。
1 脓毒症PICS
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危重症如烧伤，通过局部和全身持续释放损伤相关模式分子、细胞因子、髓样抑制细胞，造成顽固性炎症反应和免疫抑制，最终导致PICS[7]。目前脓毒症的防治策略仅解决PICS三联征某一方面的问题[7]，而PICS三联征既互相联系又互相制约。炎症反应可诱导骨髓造血干细胞优先向髓样细胞分化，产生免疫抑制性和不成熟的炎性髓样细胞[8]，同时淋巴细胞和红细胞产生减少[9]；而为了平衡炎症反应，抗炎细胞因子释放增加，最终导致或加重免疫麻痹[10]。大量炎性细胞因子和应激激素的释放造成高分解代谢，能量消耗增加，肌肉蛋白分解；而免疫麻痹又受到高分解代谢的影响。PICS代谢异常不仅限制器官中的实质细胞，而且涉及各种免疫细胞，使其糖酵解、氧化磷酸化和脂肪酸β氧化通路活性降低，加重免疫麻痹；反过来，PICS“免疫麻痹”能够引起代谢紊乱[11]，免疫细胞的异常代谢还可介导免疫炎症性反应失调，抗感染能力下降，继发持续性炎症反应。因而免疫麻痹是PICS“炎症”“免疫”和“代谢”三联征的核心问题。
2 脓毒症的免疫麻痹状态
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脓毒症患者伴随天然和获得性免疫反应的缺失，导致持续性免疫麻痹。脓毒症导致免疫麻痹至少通过以下机制：首先，淋巴结、脾、肠道、肺及其他器官的T淋巴细胞和B细胞出现大量凋亡性缺失，造成免疫反应不全，主要表现为T淋巴细胞功能障碍，以及调节性T细胞(regulatory T cells，Tregs)数量增加、功能增强；其次，脓毒症时巨噬细胞和树突状细胞发生功能障碍和损耗，导致向T淋巴细胞的抗原提呈受损，获得性免疫下降；第三，脓毒症时吞噬细胞的先天免疫功能下降，使机体对病原菌的抵抗力显著减弱[12]；第四，感染可使骨髓中粒细胞迅速脱边源化，顺着趋化因子梯度到达感染灶，同时引起骨髓干细胞扩增，代价是淋巴细胞和红细胞生成受到抑制，造成淋巴细胞缺乏和贫血[9]。感染还可诱导骨髓造血干细胞优先向髓样细胞分化，产生髓样免疫抑制性细胞(myeloid derived suppressor cells，MDSCs)，继而产生炎性介质如一氧化氮和活性氧等，导致持续性炎症反应[13]。
3 脓毒症时T淋巴细胞发生代谢重编程导致免疫麻痹
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3.1 脓毒症时T淋巴细胞发生代谢重编程
免疫细胞的代谢状态及营养素感受通路严重影响T淋巴细胞的免疫功能，因而对脓毒症具有潜在的治疗价值。危重症时激活的免疫细胞主要依靠葡萄糖作为能量来源，代偿性地从氧化磷酸化转换为糖酵解，在乳酸脱氢酶(lactate dehydrogenase，LDH)的作用下生成乳酸，迅速释放ATP，称为代谢重编程[14]。危重症时即使在有氧情况下，糖酵解仍占主导地位，称为有氧糖酵解，导致T淋巴细胞的免疫功能发生变化，从促炎表型转化为抗炎或免疫调节表型[14]，但并不能直接影响脓毒症死亡。脓毒症时失能T淋巴细胞在代谢方面存在明显缺陷，从糖酵解重编程为脂肪酸氧化磷酸化，后者是淋巴细胞失能/耗竭的重要特征[15]。
3.2 脓毒症时有氧糖酵解对T淋巴细胞功能的影响及其信号转导机制
有研究显示，调控糖酵解活性可精确调控T淋巴细胞的功能：(1)通过操纵糖酵解信号通路的关键分子可影响T淋巴细胞的功能。哺乳动物雷帕霉素靶蛋白(mammalian target of rapamycin，mTOR)可将内环境信号，如营养素、电荷和生长因子整合起来，促进细胞合成代谢和生长。(2)T淋巴细胞激活时可通过丝氨酸/苏氨酸激酶(serine/threonine kinases，Akt)-mTOR信号通路促进糖酵解[16]，减少脂质氧化[17]。mTOR可通过激活缺氧诱导因子和癌基因Myc促进糖酵解。
T淋巴细胞受体(T cell receptor，TCR)[14]、共刺激分子CD28、细胞因子白细胞介素(IL)-7和葡萄糖转运蛋白1(glucose transporter，GLUT1)[18]都能调节T淋巴细胞对葡萄糖的摄取，调控葡萄糖代谢，从而在免疫反应和淋巴细胞稳态调控中发挥重要作用。以上分子主要通过磷脂酰肌醇-3激酶(phosphatidylinositol 3-kinase，PI3K)-Akt信号通路维持糖酵解。炎症反应可激活T淋巴细胞上的CD28分子，导致Akt磷酸化，后者上调GLUT并促进其转移到细胞膜，促进葡萄糖摄入；同时还可增加多种糖酵解酶的活性。糖酵解酶通过调控转录因子调节T淋巴细胞的能量代谢，促进效应T淋巴细胞增殖和细胞因子分泌。相反，糖代谢障碍可降低T淋巴细胞的活性和功能[19]。有研究发现，IL-7可促进脓毒症患者外周T淋巴细胞mTOR的激活、GLUT1的表达以及葡萄糖的摄入，以此促进T淋巴细胞的增殖[20]。
单磷酸腺苷依赖的蛋白激酶(adenosine mono-phosphate activated protein kinase，AMPK)是免疫细胞能量代谢重编程的负性调控分子，在体内抑制脓毒症的发生[21]。从机制上，AMPK缺失可提高丙酮酸激酶依赖的有氧糖酵解，导致单核巨噬细胞释放晚期炎性因子。因此，激活髓样细胞中的AMPK可保护脓毒性休克和多重感染动物，而敲除髓样细胞AMPKα基因可加速脓毒症死亡[22]。T淋巴细胞中的AMPK可被免疫和环境因素(如营养缺乏)激活。免疫信号可通过TCR-CD3和Ca2+信号通路激活AMPKα。AMPK可通过控制T淋巴细胞的代谢可塑性而调节T淋巴细胞代谢，从而在记忆T淋巴细胞发生、细胞因子产生和抗肿瘤反应中发挥不同的作用[23]。AMPK负性调控T淋巴细胞中mTOR复合物1的活性，在营养缺乏时抑制其mRNA翻译成蛋白。激活的AMPK可在翻译水平减少效应T淋巴细胞γ干扰素(IFN-γ)的产生，以降低效能为代价，减少用于蛋白合成的能量消耗[24]。
此外，TCR信号转导可提高丙酮酸脱氢酶激酶1(pyruvate dehydrogenase kinase 1，PDHK1)的活性，使丙酮酸脱氢酶(pyruvate dehydrogenase，PDH)失活，从而抑制丙酮酸进入线粒体，促进其经糖酵解分解为乳酸；相反，LDH调控细胞因子的合成，在有氧糖酵解受阻时抑制细胞因子mRNA的转录[14]。营养代谢和生长因子信号转导是高度整合的过程，其中糖酵解产生的ATP作为一种变阻器，在T淋巴细胞免疫调控中校准PI3K-Akt-叉头框蛋白O1(forkhead box protein O1，FOXO1)信号通路。免疫信号通过PI3K信号通路激活CD8+ T淋巴细胞上的LDH。反过来，敲除LDH可抑制PI3K依赖的Akt及其转录因子靶点FOXO1，导致抗菌能力缺乏。LDH缺乏可减轻细胞氧化还原反应，减少效应T淋巴细胞ATP的产生，减弱PI3K信号转导[25]。
3.3 危重症时T淋巴细胞代谢障碍引起免疫麻痹
危重症时激活的免疫细胞主要依靠葡萄糖作为能量来源进行“代谢重编程”。脓毒症时，T淋巴细胞无论在基础状态还是在刺激下，都不能发生糖酵解或氧化磷酸化，因此不能产生ATP和表达GLUT1[12]。由于这些T淋巴细胞对葡萄糖的摄取减少，导致T淋巴细胞增殖和IFN-γ产生减少[18]，甚至幼稚T淋巴细胞的萎缩和死亡，引起免疫麻痹。
4 脓毒症时内源性GLP-1分泌的病理意义和GLP-1抵抗假说
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4.1 GLP-1分泌的病理意义
近年来，内源性GLP-1在危重症中的预警作用越来越引起重视。脓毒症[26-27]、代谢综合征或危重症患者[26,28-29]的血浆GLP-1水平急剧升高，且与炎症标志物和病情严重程度密切相关[28]，可以独立预测危重患者的预后[29]。脓毒症患者入院2~4 d，血培养阳性的革兰阳性细菌而并非革兰阴性细菌引起GLP-1系统高度激活，并与升高的先天免疫标志物可溶性CD14(soluble subtype of CD14，sCD14)、降钙素原和乳酸相关[30]。研究发现，烧伤患者入院时血浆GLP-1水平是健康志愿者的8.35倍，且随着烧伤面积的增大而增高，入院GLP-1水平是1年内死亡的危险因素之一[31]。
危重症时升高的GLP-1可促进胰岛素分泌，导致血糖下降[32]，有利于降低PICS的高分解代谢，减轻炎症反应，但其免疫抑制作用同时会引起免疫麻痹。炎性因子可刺激小鼠小肠分泌GLP-1[28-29]，其中IL-6是产生GLP-1必需的炎性因子[26,28,33]。给IL-6缺陷小鼠注射细菌内毒素脂多糖，其血浆GLP-1水平较野生型小鼠明显降低[27]。尽管如此，对于IL-6是否促进GLP-1的分泌仍存在争议。有研究发现，小鼠小肠缺血再灌注后15 min血浆GLP-1水平迅速升高，而此时血清IL-6水平刚刚可以检测到[27]。更直接的证据是给小鼠体内注射IL-6并不能增高血浆GLP-1水平，IL-6也不能刺激小肠GLUTag细胞(产生GLP-1的肠道L细胞系)分泌GLP-1[34]。
4.2 脓毒症GLP-1抵抗假说
对于脓毒症GLP-1水平升高的病理机制，笔者推测最初肠道释放GLP-1可能是机体的一种保护作用，以对抗PICS；但GLP-1持续升高可能与中枢GLP-1信号转导受阻有关。内源性GLP-1通过迷走传入神经到达中枢，与下丘脑的GLP-1受体(GLP-1 receptor，GLP-1R)结合后，与下丘脑调控摄食和能量代谢的神经元相互作用，共同调控外周能量代谢。Zhou等[35]对严重脑外伤患者伤后14 d内的代谢指标进行动态观察，结果显示，死亡组GLP-1水平较存活组明显升高，而胰岛素水平保持不变甚至在伤后第4~7天明显下降，血糖水平持续上升。Zhang等[36]发现，15%体表面积烫伤小鼠出现神经生物学改变和神经功能障碍。由于在PICS时已经出现脓毒性脑病，因此IL-6刺激肠道分泌的GLP-1向中枢的信号转导受阻，不能通过下丘脑促进胰腺分泌胰岛素，一方面造成血糖水平持续升高，另一方面造成GLP-1在血浆不断积聚而水平升高。脓毒症GLP-1水平持续升高的病理机制仍需进一步探究。
5 GLP-1可能参与PICS的发生和发展
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5.1 GLP-1对PICS血糖的调节
多种因素导致脓毒症患者血浆GLP-1水平急剧增高，且与血糖水平一致，提示GLP-1可能参与调控PICS的高分解代谢。CCI患者住院期间PICS的标志性炎症和免疫因子、代谢分子水平(包括GLP-1)等较快速恢复患者明显升高，且与长期预后相关[2,29]。有研究发现，危重症时各种炎性因子和内毒素可刺激小肠分泌GLP-1，促进胰岛素分泌，降低应激性高血糖[27]。有临床研究提示，输注外源性胰泌素对控制血糖有潜在的作用[37]。
5.2 GLP-1对PICS免疫抑制的调节
人和小鼠的T淋巴细胞[38]及小肠上皮间淋巴细胞(intraepithelial lymphocyte，IEL)[39]上都有功能性GLP-1R的表达。GLP-1R在Tregs上表达最高，阳性细胞率可达29%~34%[40]。激活T淋巴细胞能够触发人CD4+ T淋巴细胞表达功能性GLP-1R[40]。有研究发现，利拉鲁肽(GLP-1R激活剂)体内注射30 d能够增加糖尿病小鼠脾Tregs的数量[41]，在体外可抑制CD4+和CD8+ T淋巴细胞增殖，促进Tregs上抗程序性死亡受体-1(anti-programmed cell death-1，PD-1)和抗程序性死亡受体配体-1(PD-L1)的表达，从而提高Tregs的免疫抑制能力[40]。但Ji等[42]发现，GLP-1长效类似物Exendin-4在体外并不影响T淋巴细胞的增殖，而是通过交感神经通路抑制烧伤小鼠T淋巴细胞的免疫功能。
GLP-1由肠道L细胞分泌，由于L细胞可感受病原菌，因此肠道菌群可以影响肠道GLP-1的分泌，继而调节局部和全身免疫反应。在体外，Exendin-4可促进IEL的cAMP积聚，抑制激活的IEL产生细胞因子[39]。在体内，GLP-1R激动剂通过小肠IEL上的GLP-1R抑制IEL的功能，从而以蛋白激酶A(protein kinase A，PKA)依赖的方式减弱远端TCR信号转导，最终选择性地控制T淋巴细胞引起的小肠局部和全身炎症反应[43]。
有研究显示，利拉鲁肽可通过抑制小鼠T淋巴细胞增殖而缓解T淋巴细胞依赖性肾毒性血清肾炎症状，分析原因可能与其阻断T淋巴细胞糖酵解、抑制GLUT1 mRNA的表达有关[6]。因此采用GLP-1R竞争性拮抗剂，探讨PICS中内源性GLP-1对T淋巴细胞的免疫调控作用迫在眉睫。
5.3 GLP-1对PICS炎症反应的抑制作用
虽然脾、胸腺和外周淋巴结中GLP-1R表达较弱[44]，在GLP-1R激活时反应也不强烈，但是造血干细胞来源的免疫细胞系仍是GLP-1R激动剂抗炎作用的潜在靶点[43]。除降低血糖外，脓毒症GLP-1水平升高可能抑制PICS炎症反应。胰泌素可抑制脓毒症动物模型免疫细胞激活以及促炎细胞因子的释放，减轻器官功能障碍和减少死亡[37]；GLP-1R激活剂能够减弱多重Toll样受体激动剂引起的血浆肿瘤坏死因子(TNF)-α水平的升高，但该作用需要中枢α1-肾上腺素能、δ-阿片肽和κ-阿片肽受体的信号介导，提示GLP-1R激活剂的抗炎作用必须经过中枢而产生效应。在多重感染脓毒症动物模型中，GLP-1R激动剂也需要中枢GLP-1R参与以减轻脓毒症相关的不良反应[45]。
GLP-1对危重症的治疗作用也部分归功于其抗炎作用。GLP-1及其长效类似物可抑制细胞因子的分泌[32]，减少单核细胞在血管壁的聚集以及向脂肪组织的浸润。经鼻给予Exendin-4可改变程序性坏死介导的先天免疫反应，以mTOR依赖的方式改善脓毒症模型大鼠的内毒素血症、神经行为及大脑病理组织学变化[46]。但在某些情况下，GLP-1也能对脓毒症小鼠产生促炎作用[39,47-48]。Zhang等[49]发现，Exendin-4在体外可促进烧伤小鼠单核细胞TNF-α的释放，其原因可能与烧伤后单核细胞上GLP-1R信号转导由G蛋白刺激性α亚基(Gsα)向抑制性α亚基(Giα)偏移有关，从而促进丝裂原活化蛋白激酶(mitogen-activated-protein-kinase，MAPK)-TNF-α促炎信号的转导，导致炎症反应[50]。但临床上接受GLP-1类似物治疗的糖尿病患者会发生急性胰腺炎，是否与Gsα/Giα偏移相关尚需进一步探究[51]。
6 内源性GLP-1对脓毒症的免疫调控
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虽然外源性GLP-1的免疫调控作用已有报道，但截至目前，内源性GLP-1对脓毒症病情转归是利是弊尚不清楚，对获得性免疫如T淋巴细胞的免疫代谢调控也未见报道。由于危重症时T淋巴细胞被激活，对葡萄糖消耗增加而产生有氧糖酵解，因此有研究认为，脓毒症时GLP-1水平的升高可能代表能量代谢向有氧糖酵解转换，是反映PICS病理状态的一种代谢指标[29]。由此提出如下假设：脓毒症时急剧升高的内源性GLP-1可能通过T淋巴细胞上的GLP-1R，激活PI3K-Akt-mTOR通路，促进T淋巴细胞发生代谢重编程，从而调控T淋巴细胞免疫功能，防止免疫麻痹。GLP-1调控脓毒症T淋巴细胞功能障碍的免疫代谢机制如图1所示。
7 总结与展望
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院内死亡中1/3是由脓毒症导致的[39]，即使是幸存者也处于PICS的慢性免疫抑制状态。关注脓毒症GLP-1对PICS的调节有助于阐明脓毒症免疫麻痹的代谢机制。脓毒症时内源性GLP-1水平的升高作为高血糖负反馈机制，不仅可降低血糖，还可提高T淋巴细胞对葡萄糖的摄取，增加T淋巴细胞的能量供应；但若机体免疫反应过度或持续过久，由于葡萄糖缺乏，反而造成T淋巴细胞对葡萄糖的摄入减少，能量代谢降低，导致免疫麻痹。危重症可激活机体内源性免疫负调控系统，如GLP-1/GLP-1R；在适当的时间窗给予适当剂量的外源性GLP-1类似物，不仅可降低血糖，还能减轻炎症反应，并通过促进T淋巴细胞对葡萄糖的摄取，改善其免疫功能。此外，内源性GLP-1较IL-6和降钙素原对机体炎症反应敏感[3]，可用于脓毒症炎症反应的快速诊断。
基金
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  • 国家自然科学基金面上项目(82172125)
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参考文献 引证文献
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doi: 10.11855/j.issn.0577-7402.1112.2024.0813
  • 接收时间：2023-08-20
  • 首发时间：2025-10-30
  • 出版时间：2025-04-28
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  • 收稿日期：2023-08-20
  • 录用日期：2024-03-22
基金
National Natural Science Foundation of China(82172125)
国家自然科学基金面上项目(82172125)
作者信息
    1解放军总医院第四医学中心急诊医学科，北京 100048
    2解放军总医院医学创新研究部创伤修复与组织再生研究中心，北京 100853

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