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Müller 细胞介导的 IL-17 信号通路与糖尿病视网膜病变之间关系的研究进展

Research progress on the relationship between Müller cell-mediated IL-17 signaling pathway and diabetic retinopathy

来源期刊： 眼科学报 | 2024年10月 第39卷 第10期： 512-519 发布时间：2024-10-28 收稿时间：2024/11/6 15:06:01 阅读量：520
作者：
黄姗姗,
段芳,
关键词：
糖尿病视网膜病变Müller细胞白介素-17核因子-κB激活剂1
diabetes retinopathy Müller cell IL-17 Act1
DOI：
10.12419/24070105
收稿时间：
2024-07-01 
修订日期：
2024-08-30 
接收日期：
2024-10-20 
糖尿病视网膜病变(diabetes retinopathy, DR)是糖尿病常见的眼部并发症，其病理过程复杂，涉及多种细胞及炎症因子。Müller细胞作为视网膜主要支持细胞，在DR中不仅产生白介素-17(interleukin-17, IL-17)，还作为其主要靶点发挥作用，通过谷氨酸代谢异常、血管内皮生长因子(vascular endothelial growth factor, VEGF)分泌增加及调控参与DR的病理过程，加重炎症反应。IL-17主要由辅助性T细胞17(T helper cell 17, Th17)分泌，通过促进多种炎症介质(如细胞因子、趋化因子和金属蛋白酶)的分泌，增强炎症反应，导致视网膜微血管损害和神经元凋亡，促进DR的发展。高糖环境下，Müller细胞功能受损，IL-17进一步加剧其功能障碍形成恶性循环。研究表明，阻断IL-17及核因子-κB激活剂1(Nuclear factor-kappa B activator 1, Act1)/肿瘤坏死因子受体关联因子6(tumor necrosis factor receptor associated factor 6, TRAF6)/核因子-κB(Nuclear factor-kappa B, NF-κB)信号通路可减轻DR的病理改变，为DR的治疗提供了新的思路。因此，深入研究IL-17与Müller细胞在DR中的相互作用机制，对于研究该疾病的发病机制及开发精准有效的治疗策略具有重要意义。
Diabetes retinopathy (DR) is a common ocular complication of diabetes, characterized by a complex pathological process involving multiple cells and inflammatory factors. Müller cells, as the primary supporting cells of the retina, not only produce interleukin-17 (IL-17) but also serve as a primary target in DR. They participate in the pathological process of DR by contributing to abnormal glutamate metabolism, increased secretion of vascular endothelial growth factor (VEGF), and regulatory functions, thereby exacerbating the inflammatory response. IL-17 is primarily secreted by T helper cell 17 (Th17) cells and enhances the inflammatory response by promoting the secretion of various inflammatory mediators (such as cytokines, chemokines, and metalloproteinases), leading to retinal microvascular damage and neuronal apoptosis, which accelerates the progression of DR. In a high-glucose environment, Müller cell function is impaired, and IL-17 further exacerbates this dysfunction, creating a vicious cycle. Studies have shown that blocking the IL-17 and Act1/TRAF6/NF-κB signaling pathways can mitigate the pathological changes associated with DR, providing new insights for the treatment of this disease. Therefore, conducting in-depth research on the interaction mechanism between IL-17 and Müller cells in DR is of great significance for exploring the pathogenesis of this disease and developing precise and effective treatment strategies.

文章亮点

1. 关键发现

 • 本文总结了 IL-17 与 Müller 细胞在糖尿病视网膜病变 (diabetes retinopathy, DR) 中的相互作用机制及研究进展，探索未来治疗 DR 的新方法。

2. 已知与发现

 • 在高糖环境下 Müller 细胞参与 IL-17 诱发的炎症反应加速 DR 进展，引发视网膜损伤。其中核因子 -κB 激活剂1(Nuclear factor-kappa B activator 1, Act1)/ 肿瘤坏死因子受体关联因子 6(tumor necrosis factor receptor associated factor 6, TRAF6)/ 核因子 -κB(Nuclear factor-kappa B, NF-κB) 信号通路其重要作用。

3. 意义与改变

 • 抗 IL-17A 单克隆抗体、信号通路抑制剂以及炎症相关因子的基因敲除技术可能成为 DR 的新疗法，有望替代目前的视网膜激光治疗和抗 VEGF 药物，降低相关并发症风险。
       糖尿病视网膜病变(diabetes retinopathy, DR)是以视网膜内微血管炎症性改变为病变特点的糖尿病眼部并发症。DR患者常出现视力下降、屈光改变、对比敏感度下降、视野缺陷等症状，严重时可致盲。在中国，DR的患病率约为16.3%，发病年龄主要集中在18~74岁[1]。全球糖尿病患者中DR患病率约为34.6%，其中威胁视力的DR患病率约为10.2%，超过50%由DR导致视力损伤或致盲的病例分布在亚太地区[2-3]。DR的病理改变主要包括血视网膜屏障(blood-retinal barrier, BRB)破坏、视网膜新生血管形成、视网膜谷氨酸代谢功能障碍和视网膜神经元凋亡等[4-7]，其发病机制复杂，涉及多元醇途径、蛋白激酶C(protein kinase C, PKC)激活、氧化应激、晚期糖基化终产物AGEs(advanced glycation end products, AGEs)形成、生长因子和黏附分子表达增加等[8- 9]。研究表明，DR中白介素-1β(Interleukin-1β)、肿瘤坏死因子-α(Tumor Necrosis Factor-α, TNF-α)、IL-6、IL-8和单核细胞趋化蛋白-1(monocyte chemotactic protein 1, MCP-1)等炎症因子的表达增加[10-11]，最新研究显示IL-17在1型及2型糖尿病的患者血液中均有增加[12-13]。Byrne等[14]进一步证实IL-17 的调节紊乱影响DR的进展。
       目前缺乏IL-17在DR中作用机制的总结[6, 15]，因此本文系统性地综述IL-17与DR之间的复杂关系及其可能机制，旨在更深入地理解免疫介导的炎症因子如何参与并驱动DR的发生与发展，为探索和开发针对该疾病精准有效的治疗策略提供理论基础。

1 Müller细胞在DR的过程中参与炎症反应

       Müller细胞作为主要的大神经胶质细胞和视网膜支持细胞，横跨整个视网膜，从内界膜到外界膜，支持光感受器和神经元的存活，在调节免疫应答与炎症反应方面扮演着不可或缺的角色，确保视网膜微环境的和谐与平衡[16- 17]。Müller细胞通过提供营养因子、清除代谢废物、控制细胞外空间体积和离子和水的稳态，参与视觉循环、释放神经递质、调节BRB功能[18-20]，是促炎信号的主要细胞靶点。在高糖情况下，Müller细胞应激及反应标志物胶质纤维酸性蛋白(glial fibrillary acidic protein, GFAP)增加[21]，谷氨酰胺合成酶水平降低[22]，Müller细胞迁移能力增强，进而释放大量促血管生成因子及促纤维化因子，介导视网膜炎症、氧化应激、血管渗漏和新生血管[17, 23-27]。Müller细胞还是DR炎症因子的主要来源[7, 22, 28]，通过自分泌信号级联增强视网膜中的炎症和神经元凋亡[29]。此外，异常的Müller细胞增殖和促纤维化介质的释放在纤维增生性组织的形成中起关键作用[30]。因此，DR导致的Müller功能失调可能使炎症反应进一步加重。

2 IL-17促进炎症反应加速DR进展

       IL-17是导致DR发生与发展的重要炎症因子，IL-17A是IL-17家族中被研究得最广泛的成员，具有强烈的促炎作用[31-32]，其主要来源于辅助性T细胞17(T helper cell 17, Th17)。Th17是一种特定的CD4+ T细胞亚群，以分泌IL-17为主要特征，在宿主防御、炎症反应和自身免疫疾病中发挥重要作用[31]。IL-17通过促进多种炎症介质(如细胞因子、趋化因子和金属蛋白酶)的分泌，增强炎症反应。IL-17A和Th17还参与多种类型的糖尿病[33- 34]。在DR中，IL-17不仅通过下调紧密连接蛋白、激活人类酪氨酸激酶蛋白1(janus kinase1, JAK1)加重炎性细胞浸润等多种机制破坏BRB，还诱导内皮细胞分泌炎症因子，导致视网膜血管的渗漏和炎性细胞的浸润[14, 35]。同时，IL-17调控糖尿病中的中性粒细胞表达，参与DR的血管渗漏[29]。Yan等[36]报道指出，IL-17A在2型糖尿病小鼠非增殖性糖尿病视网膜(proliferative diabetic retinopathy, PDR)病变中起关键作用，抑制Th17分化对PDR具有保护作用。IL-17A-/-小鼠中，糖尿病介导的视网膜炎症、氧化应激等反应强度均显著降低[37]。IL-17A水平升高可导致视网膜局部炎症和免疫反应，通过影响视网膜细胞功能而加重DR病情[38]。

3 Müller细胞参与IL-17诱发的炎症反应加速DR进展

       IL-17A加速BRB破坏的作用，可能是通过在DR过程中促进Müller细胞功能损伤来实现的。在视网膜中因为BRB的存在，淋巴细胞较少。因此，IL-17在视网膜中主要由Müller细胞产生[15]。已有实验证据表明，IL-17参与DR的过程，Müller细胞的激活不仅分泌IL-17A，还作为IL-17效应的靶点发挥作用[15, 39]。高血糖环境下，Müller细胞会释放大量炎性细胞因子。IL-17A可以与其表达在Müller细胞、光感受器和视网膜内皮细胞上的受体A(IL-17RA)结合，形成异二聚体受体复合物，通过核因子-κB(Nuclear factor-kappa B, NF-κB)激活剂1 (Act1)激活下游信号通路，最终触发促炎细胞因子TNF-α、IL-1、IL-6和趋化因子C-X-C化学家族配体5(Chemokine C-X-C Motif Ligand 5, CXCL5)、趋化因子(Chemokine ligand, CCL)2、CCL7 和 CCL20的产生及新生血管的形成[40]，这些细胞因子及新生血管反过来促进Müller细胞等中枢神经系统常驻细胞的激活，导致趋化因子的进一步分泌和炎症细胞的募集进入中枢神经系统，引起弥散性中枢神经系统炎症，形成恶性循环[39]，导致视网膜微血管的损害，引发功能丧失[34, 37, 41]。体外实验表明，高糖刺激下Müller细胞中的晚期糖基化终末产物受体(receptor of advanced glycation endproducts, RAGE)呈现过表达状态，此类受体与配体结合后，可激活丝裂原活化蛋白激酶(mitogen-activated protein kinase, MAPK)信号转导通路，进而上调促炎性细胞因子的基因表达水平[42]。因此在DR的发病机制中，Müller细胞介导的IL-17分泌增加在炎症反应中发挥重要作用。

4 Müller细胞介导的IL-17在DR发展中主要机制

       在DR中，Müller细胞通过介导IL-17信号通路参与视网膜的炎性反应和病理改变。具体机制包括以下几个方面。

4.1 谷氨酸代谢异常

       Müller细胞通过谷氨酰胺合成酶( glutamine synthetase, GS)将谷氨酸转化为谷氨酰胺，从而消除高浓度谷氨酸对神经元的毒性。高糖、缺血缺氧和高游离脂肪酸等因素可导致Müller细胞功能受损，GS表达下调，谷氨酸转运受阻，进而引起谷氨酸积累、激活神经毒性信号转导途径最终导致神经元细胞凋亡[43-44]。在DR中，IL-17A加重了高糖和糖尿病诱导的Müller细胞活化和功能障碍引起谷氨酸水平升高，谷氨酰胺合成酶和兴奋性氨基酸转运蛋白-1表达降低[15]。

4.2 血管内皮生长因子分泌增加

       血管内皮生长因子(vascular endothelial growth factor, VEGF)在DR新生血管的形成中起重要作用。研究表明，Müller细胞在高糖环境下可分泌更多的VEGF，进一步促进新生血管的形成和视网膜病变的发展，而IL-17可能通过激活Müller细胞中的信号通路，上调VEGF的表达和分泌，从而加剧DR的病理改变[23, 45]。

4.3 Act1/TRAF6/NF-κB信号通路的调控

       Act1是IL-17下游信号通路中重要的激活因子，在体液免疫和自身免疫中都发挥重要作用，在炎性疾病中通过调节免疫细胞调控炎症的功能，且被认为是IL-17信号传导的主要介质[18, 46-47]。Act1同时也是炎症传导通路中重要的细胞内蛋白，能够同时激活NF-κB和JNK，其过表达可导致上皮细胞系中NF-κB和JNK的激活[19-20]，诱导多种促炎基因的表达，包括细胞因子(如TNF-α、IL-1β)、趋化因子(如CXCL1、CXCL2)和金属蛋白酶，如基质金属蛋白酶(matrix metalloproteinase, MMP)-9[48]。在DR中，Th22浸润到视网膜分泌IL-22，IL-22结合IL-22Rα1激活Act1/TRAF6信号通路，促进视网膜上皮细胞的炎症，参与DR的发病过程[49]。视网膜内皮细胞死亡发生在IL-17A/IL-17R上，有Act1/FADD信号级联，导致caspase介导的细胞凋亡[34]。因此推测Act1在介导DR引起的视网膜病变中发挥重要作用。
       TRAF6是免疫及炎症反应中一个重要的靶点[50]，可作为E3泛素连接酶起作用。研究发现TRAF6在IL-1R的刺激下诱导NF-κB激活[51]，而IL-17R家族和Act1在其细胞内区域与IL-1R结构域具有序列同源性[52]。此外，TRAF6基因敲除小鼠中的IL-17不能激活NF-κB和JNK[53]，提示TRAF6与Act1结合参与IL-17介导的炎症反应[54-55]。有报道指TRAF6在DR患者中表达上调，表明该因子在促进DR炎症的发生和发展中至关重要[56-57]。
       NF-κB是一种蛋白质复合物，几乎存在于所有类型的细胞中，是促炎基因表达的关键调控因子之一[58]，参与感染、炎症等应激反应的发生。NF-κB通路的组成性激活通常与炎症性疾病相关，当细胞暴露于各种细胞外刺激时被迅速激活[59]，引起抑制蛋白κB(Inhibitor of kappa B, IκB)的快速磷酸化、泛素化和最终的蛋白水解降解，从而释放NF-κB转移到细胞核，调节炎症相关基因的转录[60]。NF-κB的激活导致促炎细胞因子、趋化因子和VEGF等血管生成因子的产生，这些因子会引起眼底炎症和新血管的形成[61]。同时有研究表明NF-κB在DR患者中被激活，引起炎症及凋亡反应的发生[62]。
       最近的研究揭示了IL-17信号通路的新调控机制。κB抑制因子激酶(inhibitor of kappa B kinase, IKK)相关激酶(如TBK1和IKKi)通过磷酸化Act1，减弱其与TRAF6的结合能力，从而抑制IL-17诱导的NF-κB激活。有报道指在高糖诱导下，糖尿病小鼠视网膜中的IL-17A通过Act1/IKK信号通路加剧Müller细胞激活和功能障碍；另外，与IL-17RA相关的Act1/TRAF6/IKK/NF-κB信号通路调节DR中IL-17A对Müller细胞的损伤，使用抗IL-17RA抗体可缓解高糖诱导的Müller细胞功能障碍，Act1敲低阻断了的下游信号激活，改善视网膜血管损伤和神经元细胞凋亡[15, 39]。有研究学者通过使用链脲佐菌素(Streptozocin, STZ)诱导糖尿病小鼠模型进行体内研究，比较野生型小鼠(C57BL/6)和IL-17A缺失小鼠(IL-17A-/-)的视网膜毛细血管退化情况，显示糖尿病诱导的视网膜毛细血管退化在IL-17A-/-小鼠中显著降低，视网膜内皮细胞死亡通过IL-17A/IL-17R /Act1/FADD信号级联反应发生，导致caspase介导的细胞凋亡[34]。STZ诱导DR小鼠模型中，NR2E3基因过表达可降低DR中炎性因子(TNF-α、IL-1β和IL-6)和细胞凋亡水平，同时抑制IL-17和Act1的表达，得出NR2E3通过调控芳香烃受体(aryl hydrocarbon receptor，AHR)/IL-17A通路抑制炎症和凋亡[63]。因此，推测Müller细胞在IL-17诱导的DR中发挥重要作用，其中IL-17/Act1相关的信号通路占主导作用。

图 1 高糖情况下Müller细胞介导IL-17信号通路的主要机制
Figure 1 The main mechanism of Müller cells mediating IL-17 signaling pathway under high glucose conditions
该图通过BioRender.com创建。
This graph was created by BioRender.com.

5 总结与展望

       综上所述，Müller细胞在DR的过程中通过应激反应标志物GFAP增加、谷氨酰胺合成酶水平降低等加剧炎症反应；IL-17作为重要炎症因子通过促进多种炎症介质释放加重DR进展；Müller细胞作为主要参与者通过谷氨酸代谢异常、VEGF分泌增加、Act1/TRAF6/NF-κB信号通路的调控参与IL-17诱发的炎症反应。其中IL-17/Act1相关的信号通路占主导作用[64]，糖尿病患者外周血和眼房水IL-17A水平升高与DR风险相关，提示IL-17A及其下游信号通路(如Act1/TRAF6/IKK/NF-κB)可作为DR治疗的新靶点。抗IL-17A可能是治疗PDR的良好候选药物[65]，另外抗IL-17A单克隆抗体或IL-17信号通路抑制剂以及炎症相关因子的基因敲除技术可能成为治疗DR的新兴疗法。
       目前，临床上对DR的治疗主要包括视网膜激光光凝术(panretinal photocoagulation, PRP)、抗VEGF药物、玻璃体切割术(pars plana vitrectomy, PPV)以及糖皮质激素药物治疗等，但上述治疗方法存在黄斑水肿、白内障、青光眼等并发症的风险[11, 66]。
       因此，通过阻断IL-17A或其信号通路，有望有效减轻糖尿病患者视网膜的炎症反应和病理损伤。对Müller细胞及IL-17在DR病程中的炎症作用及其与视网膜细胞动态平衡的关系进行深入研究，将为DR及其他眼部炎症性疾病的治疗提供坚实的实验和理论基础。

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