通窍活血汤含药脑脊液通过抑制血浆纤维蛋白原介导的 NLRP3炎性小体活化减轻氧糖剥夺/复糖复氧诱导的神经元损伤

doi:10.12122/j.issn.1673-4254.2026.07.08

南方医科大学学报 ›› 2026, Vol. 46 ›› Issue (7): 1543-1552.doi: 10.12122/j.issn.1673-4254.2026.07.08

• • 上一篇

通窍活血汤含药脑脊液通过抑制血浆纤维蛋白原介导的 NLRP3炎性小体活化减轻氧糖剥夺/复糖复氧诱导的神经元损伤

王艳¹(), 黄平¹, 彭宇芹², 孙浩², 汪宁²^,³^,⁴(), 汪长中¹()

^1.安徽中医药大学，中西医结合学院，安徽合肥 230012
^2.安徽中医药大学，药学院，安徽合肥 230012
^3.安徽中医药大学，中药研究与开发安徽省重点实验室，安徽合肥 230012
^4.安徽中医药大学，中药复方安徽省重点实验室，安徽合肥 230012

收稿日期:2025-11-26 出版日期:2026-07-20 发布日期:2026-07-20
通讯作者: 汪宁,汪长中 E-mail:yangwangsci@163.com;wnsci123@163.com;ahwcz63@sina.com
作者简介:王艳，博士，教授，硕士生导师，E-mail: yangwangsci@163.com
基金资助:
安徽省高校优秀科研创新团队项目(2022AH010034);安徽省高等学校科学研究重点项目(2023AH050738)

Tongqiao Huoxue Decoction-medicated rat cerebrospinal fluid attenuates oxygen and glucose deprivation-induced neuronal injury by suppressing fibrinogen-mediated NLRP3 inflammasome activation

Yan WANG¹(), Ping HUANG¹, Yuqin PENG², hao SUN², Ning WANG²^,³^,⁴(), Changzhong WANG¹()

^1.School of Integrated Chinese and Western Medicine, Anhui University of Chinese Medicine, Hefei 230012, China
^2.School of Pharmacy, Anhui University of Chinese Medicine, Hefei 230012, China
^3.Anhui Provincial Key Laboratory of Research & Development of Chinese Medicine, Anhui University of Chinese Medicine, Hefei 230012, China
^4.Anhui Provincial Key Laboratory of Traditional Chinese Medicine Compounds, Anhui University of Chinese Medicine, Hefei 230012, China

Received:2025-11-26 Online:2026-07-20 Published:2026-07-20
Contact: Ning WANG, Changzhong WANG E-mail:yangwangsci@163.com;wnsci123@163.com;ahwcz63@sina.com

摘要/Abstract

摘要：

目的探讨通窍活血汤含药脑脊液（TQHXD-CSF）对氧糖剥夺/复糖复氧（OGD/R）损伤小鼠小胶质细胞（BV-2）炎症损伤的修复作用，以及其对共培养体系中神经元（HT22）细胞的保护作用。方法采用Transwell共培养体系，将BV-2细胞与HT22细胞进行共培养；对Transwell小室中BV-2细胞建立OGD/R+FIB损伤模型后，给予TQHXD-CSF干预，下层HT22细胞正常培养。通过倒置显微镜观察各组BV-2细胞形态变化；采用CCK-8法检测各组细胞存活率；流式细胞术分析细胞内活性氧（ROS）含量及细胞凋亡率；CD86/CD206免疫荧光双染法观察BV-2细胞极化表型；透射电镜结合流式细胞术鉴定并定量含纤维蛋白原（FIB）的细胞外囊泡（EVs）；Western blotting法检测NLRP3炎性体相关蛋白（NLRP3、ASC、Caspase-1、GSDMD）及炎症因子（IL-1β、IL-18）的表达水平；Pull-down实验验证FIB与NLRP3蛋白的相互作用。结果 OGD/R+FIB损伤可显著诱导BV-2细胞向M1型促炎表型极化，上调CD86表达水平，增加含FIB的EVs释放，激活NLRP3炎性体通路（P<0.01）；进而导致共培养的HT22细胞活力下降、ROS生成增多、凋亡率升高（P<0.01）。TQHXD-CSF干预后，可显著促进BV-2细胞向M2型抗炎表型极化，上调抗炎标志物CD206表达，减少含FIB的EVs分泌（P<0.01）；同时可显著抑制BV-2细胞活化介导的HT22细胞中NLRP3、ASC、Caspase-1、GSDMD、IL-1β、IL-18的蛋白表达，抑制NLRP3炎性体过度激活，明显改善HT22细胞的炎症损伤及凋亡情况（P<0.01）。Pull-down实验证实，FIB与NLRP3蛋白之间存在直接相互作用。结论 TQHXD-CSF可通过抑制OGD/R+FIB损伤后BV-2细胞释放含FIB的EVs，阻断NLRP3炎性体激活介导的炎症反应，对HT22细胞发挥保护作用，为减轻缺血性脑卒中后的神经炎症损伤提供实验依据。

关键词: 通窍活血汤, 含药脑脊液, 纤维蛋白原, NLRP3炎症小体, 细胞外囊泡

Abstract:

Objective To examine the protective effects of cerebrospinal fluid from Tongqiao Huoxue Decoction-treated rats (TQHXD-CSF) against oxygen and glucose deprivation and reoxygenation (OGD/R)-induced injury in murine BV-2 microglial cells and co-cultured HT22 cells. Methods In a Transwell co-culture system of BV-2 and HT22 cells, OGD/R+fibrinogen (FIB) injury was induced in BV-2 cells followed by treatment with TQHXD-CSF intervention, and HT22 cells in the lower chamber were cultured under normal conditions. The cells were observed for changes in cell morphology, viability, intracellular ROS level, apoptosis, M1/M2 polarization, and FIB-containing extracellular vesicles (EVs). The cellular expressions of NLRP3, ASC, caspase-1, GSDMD, IL-1β, and IL-18 were quantified using Western blotting, and FIB-NLRP3 binding was confirmed by pull-down assay. Results OGD/R+FIB injury caused polarization of BV-2 cells to the pro-inflammatory M1 phenotype, increased CD86 expression and release of FIB-containing EVs, and activated the NLRP3 inflammasome. The co-cultured HT22 cells showed reduced cell viability, elevated ROS, and increased cells apoptosis. Treatment with TQHXD-CSF promoted M2 polarization in BV-2 cells, upregulated CD206 expression, suppressed FIB⁺ EVs secretion, and inhibited NLRP3 inflammasome activation in HT22 cells, which showed significantly lowered expressions of NLRP3, ASC, caspase-1, GSDMD, IL-1β, and IL-18 proteins and hence reduced inflammatory injury and cell apoptosis. Pull-down assay confirmed direct FIB and NLRP3 binding. Conclusion In the co-culture system of BV-2 cells and HT22 cells, TQHXD-CSF treatment protects HT22 cells against OGD/R+FIB-induced injury by inhibiting FIB-containing EVs release from BV-2 cells and suppressing NLRP3 inflammasome activation.

Key words: Tongqiao Huoxue Decoction, medicated cerebrospinal fluid, fibrinogen, NLRP3 inflammasome, extracellular vesicles

王艳, 黄平, 彭宇芹, 孙浩, 汪宁, 汪长中. 通窍活血汤含药脑脊液通过抑制血浆纤维蛋白原介导的 NLRP3炎性小体活化减轻氧糖剥夺/复糖复氧诱导的神经元损伤[J]. 南方医科大学学报, 2026, 46(7): 1543-1552.

Yan WANG, Ping HUANG, Yuqin PENG, hao SUN, Ning WANG, Changzhong WANG. Tongqiao Huoxue Decoction-medicated rat cerebrospinal fluid attenuates oxygen and glucose deprivation-induced neuronal injury by suppressing fibrinogen-mediated NLRP3 inflammasome activation[J]. Journal of Southern Medical University, 2026, 46(7): 1543-1552.

图/表 9

图1 BV-2细胞与HT22细胞FIB+OGD/R造模示意图

Fig.1 Schematic illustration of fibrinogen (FIB) and oxygen and glucose deprivation and reoxygenation (OGD/R) modeling in BV-2 cells and HT22 cells.

图2 造模前后BV-2细胞的形态变化图

Fig.2 Morphological changes of BV-2 cells before and after the modeling. Arrows indicate cell polarization.

图3 TQHXD-CSF对细胞活性的影响

Fig.3 Effect of cerebrospinal fluid from Tongqiao Huoxue Decoction-treated rats (TQHXD-CSF) on cell viability (n=6). A, B: Effects of TQHXD-CSF on viability of BV-2 cells and HT22 cells. C, D: Effects of TQHXD-CSF on LDH release in BV-2 cells and HT22 cells. **P<0.01 vs Control group; ##P<0.01vs Model group.

图4 TQHXD-CSF对共培养体系中BV-2细胞极化的影响

Fig.4 Effect of TQHXD-CSF on polarization of BV-2 cells in the co-culture system (Original magnification: ×200, n=3). *P<0.05, **P<0.01 vs Control group; ##P<0.01 vs Model group.

图5 TQHXD-CSF对共培养体系BV-2细胞上清液中含FIB的EVs数量的影响

Fig.5 Effect of TQHXD-CSF on the number of extracellular vesicles (EVs) containing fibrinogen (FIB) in the supernatant of BV-2 cells in the co-culture system (n=3). A: Identification of EVs in the supernatant of BV-2 cells in the co-culture system. B: Quantitative mapping of FIB in the EVs. **P<0.01 vs Control group; ##P<0.01 vs Model group

图6 TQHXD-CSF对共培养体系HT22细胞中ROS含量的影响

Fig.6 Effect of TQHXD-CSF on the content of ROS in HT22 cells in the co-culture system (n=3). **P<0.01 vs Control group; ##P<0.01 vs Model group.

图7 TQHXD-CSF对共培养体系HT22细胞凋亡的影响

Fig.7 Effect of TQHXD-CSF on apoptosis of HT22 cells in the co-culture system (n=3). **P<0.01 vs Control group; ##P<0.01 vs Model group.

图8 TQHXD-CSF对NLRP3炎症小体相关蛋白表达的影响

Fig.8 Effect of TQHXD-CSF on expressions of proteins associated with the NLRP3 inflammasome in HT22 cells (n=3). *P<0.05, **P<0.01 vs Control group; #P <0.05, ##P<0.01 vs Model group.

图9 NLRP3能被FIB下拉产生相互作用

Fig.9 NLRP3 can be co-immunoprecipitated with FIB, indicating a physical interaction between the two proteins.

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通窍活血汤含药脑脊液通过抑制血浆纤维蛋白原介导的 NLRP3炎性小体活化减轻氧糖剥夺/复糖复氧诱导的神经元损伤

Tongqiao Huoxue Decoction-medicated rat cerebrospinal fluid attenuates oxygen and glucose deprivation-induced neuronal injury by suppressing fibrinogen-mediated NLRP3 inflammasome activation

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