NLRP3炎症小体与特发性膜性肾病的相关性研究

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NLRP3炎症小体与特发性膜性肾病的相关性研究
Research on the Correlation between NLRP3 Inflammasome and Idiopathic Membranous Nephropathy

DOI: 10.12677/jcpm.2025.42255, PDF, HTML, XML,
作者: 张宝哲, 黄兰^*：承德医学院附属医院肾脏内科，河北承德
关键词: 特发性膜性肾病；NLRP3炎症小体；终末期肾病；Idiopathic Membranous Nephropathy； NLRP3 Inflammasome； End-Stage Renal Disease

摘要: 特发性膜性肾病(IMN)是一种自身免疫性疾病，是肾病综合征的主要原因之一，由自身抗体攻击足细胞抗原导致原位产生免疫复合物而引起，该疾病表现出异质性的结果，大约30%的病例进展为终末期肾病。NLRP3炎性小体是一种细胞内多蛋白复合物，作为先天免疫系统中的重要传感器，NLRP3检测外源性致病性侵袭和内源性细胞损伤，并通过形成NLRP3炎性小体(一种激活caspase-1的超分子复合物)来做出反应。越来越多的证据表明，特发性膜性肾病的发病与NLRP3炎症小体有关。抑制NLRP3炎性小体为治疗特发性膜性肾病提供了更多的可能性。

Abstract: Idiopathic membranous nephropathy (IMN) is an autoimmune disease and one of the main causes of nephrotic syndrome. It is caused by the in- situ formation of immune complexes resulting from the attack of autoantibodies on podocyte antigens. This disease shows heterogeneous outcomes, and approximately 30% of cases progress to end-stage renal disease. The NLRP3 inflammasome is an intracellular multi-protein complex. As an important sensor in the innate immune system, NLRP3 detects exogenous pathogenic invasions and endogenous cell damage and responds by forming the NLRP3 inflammasome, a supramolecular complex that activates caspase-1. There is increasing evidence suggesting that the onset of idiopathic membranous nephropathy is related to the NLRP3 inflammasome. Inhibiting the NLRP3 inflammasome provides more possibilities for the treatment of idiopathic membranous nephropathy.

文章引用：张宝哲, 黄兰. NLRP3炎症小体与特发性膜性肾病的相关性研究[J]. 临床个性化医学, 2025, 4(2): 870-875. https://doi.org/10.12677/jcpm.2025.42255

1. 引言

膜性肾病(MN)是成人肾病综合征的常见原因。特发性膜性肾病(IMN)是MN的一种形式。IMN被描述为一种自身免疫性疾病，其发病机制相当复杂，易发生静脉栓塞、感染等并发症，近年研究发现核苷酸结合寡聚化结构域样受体蛋白3 (nucleotide-binding domain and leucine-rich repeat protein 3, NLRP3)在肾脏炎症反应过程中具有重要作用，本文旨在回顾NLRP3炎性小体在特发性膜型肾病中的重要性及其预测疾病预后指标的潜力。

2. NLRP3炎症小体的结构与功能

NLRP3是一种118 kDa胞质PRR蛋白，由多种细胞表达，包括中性粒细胞、巨噬细胞、小胶质细胞、淋巴细胞、上皮细胞、成骨细胞、神经元和树突状细胞。NLRP3 蛋白包含一个C末端富含亮氨酸重复序列(LRR)结构域、一个介导寡聚化的含中央ATP酶的NACHT (存在于NAIP、CIITA、HET-E和TP1中)结构域，以及一个募集蛋白质以形成炎性小体复合物的N末端pyrin (PYD)结构域。与其他炎性小体一样，NLRP3炎性小体复合物由传感器(NLRP3蛋白)、接头蛋白(细胞凋亡相关斑点样蛋白，ASC)和效应物(caspase-1)组成。NLRP3炎症小体是炎症的中心分子介质，通过激活Cas pase-1促进炎症细胞因子IL-1β和IL-18等分泌，导致氧化应激和慢性炎症。

3. NLRP3炎症小体的激活

NLRP3的激活包含两个关键步骤，即启动步骤与激活步骤。首先，NLRP3表达可在识别PAMP或DAMP时由PRR或参与免疫和炎症反应的细胞因子引发。激活NF-κB或其他转录因子后，NLRP3以及其他炎性小体组分的表达转录上调[1]-[4]。NLRP3的翻译后修饰(包括泛素化、磷酸化和sumoylation)也会引发NLRP3激活，同时仍使NLRP3保持自抑制状态[2]-[4]。在第二步中，NLRP3被各种微生物和无菌刺激激活，这些刺激通常会收敛到K⁺外排或其他离子变化[3] [5]-[10]。这些刺激的范围从细菌毒素(如黑合菌素)到细胞外ATP，再到微粒(如尿酸晶体、胆固醇晶体和淀粉样蛋白)。重要的是，已发现一种导致有丝分裂的丝氨酸/苏氨酸激酶NEK7 (NIMA相关激酶)通过直接结合在NLRP3激活中发挥关键作用[11]-[14]。激活后，NLRP3组装并募集下游组分以形成炎性小体复合体，激活的炎性caspase蛋白水解处理细胞因子以产生成熟形式并诱导高度炎性细胞死亡形式，称为细胞焦亡[1] [3] [9] [15]。

4. 特发性膜性肾病

MN也是原发性肾小球肾炎中终末期肾病(ESRD)的常见原因。MN的主要临床表现包括重蛋白尿 (通常为>3.5 g/d)、低白蛋白血症、不同程度的组织水肿和高脂血症[16]。MN的诊断取决于肾活检样本病理学结果，病理特征包括：光学显微镜下肾小球毛细血管壁增厚，无明显的肾小球细胞增多，免疫荧光显微镜下沿肾小球毛细血管壁显示IgG和补体C3，电子显微镜下上皮下电子致密沉积[16]-[18]。根据病因，MN可分为特发性(也称为原发性)或继发性MN [19]。PMN和SMN分别约占MN病例的75%~80%和20%~25% [17] [20] [21]。约30%的成人肾病综合征由膜性肾病综合征引起[22] [23]，特发性膜性肾病(Idiopathic membranous nephropathy, IMN)是一种抗体介导的足细胞损伤疾病，是成人肾病综合征的最常见原因之一[17] [21]。是肾病综合征的主要原因之一。MN的发病机制很复杂，核心过程是在肾小球基底膜中形成免疫复合物。目前提出，循环自身抗体及其在肾小球足细胞上的靶抗原的原位免疫复合物沉积在上皮细胞下，导致补体激活，从而破坏足细胞结构并导致蛋白尿[24]。

5. NLRP3炎症小体与IMN

Nan等[25]研究发现NLRP3炎症小体和caspase-1在IMN患者肾脏组织中高表达，在各期IMN中的表达趋势与NLRP3炎症小体一致，活化的caspase-1将生物无活性肽pro-IL-1β和pro-IL-18分别加工成其活性形式IL-1β和IL-18。同时伴有炎症因子TNF-α和IL-1β高表达。实验证据表明，针对NLRP3炎症小体的活性调控可有效缓解肥胖相关肾小球病变的早期肾损伤。在肥胖诱发的代谢紊乱背景下，NLRP3炎症小体的异常活化通过介导IL-1β和IL-18等促炎因子的成熟释放，加剧肾脏局部的炎性微环境及足细胞损伤，最终导致肾小球滤过屏障功能障碍。通过药理学手段阻断该炎症小体的活化通路，可显著降低肾小球系膜基质增生及足细胞脱落等病理改变。这一机制与NLRP3介导的线粒体氧化应激及焦亡信号通路的抑制密切相关，为肥胖相关性肾病的早期干预提供了分子靶点[26]。

5.1. 足细胞损伤方面

既往研究[27]发现NLRP3炎症小体激活后产生的炎症环境可能会直接或间接影响足细胞的功能和结构。一方面，细胞因子可以导致足细胞骨架蛋白的破坏，使足细胞形态发生改变；另一方面，炎症反应可能会干扰足细胞与基底膜之间的相互作用，导致足细胞从基底膜上脱落，从而破坏肾小球滤过屏障。NLRP3炎症小体在膜性肾病大鼠肾脏被激活，并引起炎症反应导致足细胞损伤，足细胞是肾小球滤过屏障的重要组成部分，在IMN中足细胞损伤是关键环节，IL-1β可以诱导足细胞产生氧化应激反应，导致足细胞的骨架蛋白破坏，影响足细胞的正常功能，如滤过屏障的完整性受损，从而加重蛋白尿。

5.2. 免疫调节方面

NLRP3炎症小体参与了机体的免疫调节过程。IL-8则参与并调节T细胞的活化和分化，介导其他炎性细胞因子的产生，并诱导炎症细胞活化[28]。几项研究确实发现IMN中Th17细胞表达增强，IL-17和其他细胞因子上调，这表明IMN中确实存在炎症环境。在IMN发病过程中，它可能通过调节T细胞的功能来影响免疫反应，激活的NLRP3炎症小体产生IL-8，它可以促进辅助性T细胞17 (Th17)的分化，Th17细胞分泌细胞因子IL-17等可以进一步招募炎症细胞到肾小球局部，加剧炎症反应和组织损伤[29]-[31]。

5.3. 纤维化过程

长期的炎症反应会导致肾脏纤维化。许多研究表明，NLRP3和caspase-1水平升高与CKD患者的肾纤维化有关[32] [33]，表明NLRP3炎性小体可能参与肾纤维化。我们之前的研究表明，MCC950是NLRP3炎性小体的特异性抑制剂，可以减轻顺铂诱导的肾纤维化[34]。在肺和血清中使用抗IL-1β可以降低小鼠的炎症反应并减轻肾纤维化[35]。简而言之，NLRP3炎性小体激活产生IL-1β，介导炎症反应并参与肾纤维化的早期阶段，通过激活成纤维细胞，使其产生过多的细胞外基质成分，如胶原蛋白等，促进肾脏纤维化的发展。在IMN患者中，随着病情的进展，肾脏纤维化逐渐加重，NLRP3炎症小体的持续激活可能是其中一个重要的机制。

6. 结论

因此，NLRP3炎性小体在特发性膜性肾病的发生和发展中起着复杂而重要的作用。NLRP3炎性小体已成为药物发现领域中一个有吸引力的靶点，其抑制剂对许多疾病的治疗具有很高的治疗价值。寻找具有足够药代动力学特性的有效和选择性NLRP3炎性小体抑制剂仍然存在一些障碍，需要更多的研究来进一步了解靶向该通路的化合物的结合和机制。

7. 未来展望

尽管IMN的知识和临床管理取得了重大进展，利妥昔单抗正在成为IMN的标准免疫抑制疗法，但该疾病仍表现出异质性预后。对于需要治疗干预的IMN患者，只有60%的患者在利妥昔单抗治疗的24个月期间表现出部分或完全缓解[36]，但获得的关于NLRP3炎性小体的知识需要转化为临床靶向治疗。要达到这一地位，目前对IMN的理解需要大幅度的进步。因此我们需要更好地了解特发性膜性肾病的发病机制，从而找到更有效的治疗靶点，更好地对患者进行分层，更好地评估患者的治疗效果和治疗耐药性。

NOTES

^*通讯作者。

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