Paeoniflorin Suppressed High Glucose-Induced Retinal Microglia MMP-9 Expression and Inflammatory Response via Inhibition of TLR4/NF-κB Pathway Through Upregulation of SOCS3 in Diabetic Retinopathy
Paeoniflorin Suppressed High Glucose-Induced Retinal Microglia MMP-9 Expression and Inflammatory Response via Inhibition of TLR4/NF-κB Pathway Through Upregulation of SOCS3 in Diabetic Retinopathy
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DOI：
10.1007/s10753-017-0571-z
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发表时间：
2017-06
期刊：
影响因子：
5.1
通讯作者：
Suning Zhu;Bingqian Liu;M. Hao;Yixin Fan;C. Qian;P. Teng;Xiao-Wei Zhou;Liang Hu;Wen-tao Liu;Zhi-lan Yuan;Qing-Ping Li
中科院分区：
文献类型：
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作者：
Suning Zhu;Bingqian Liu;M. Hao;Yixin Fan;C. Qian;P. Teng;Xiao-Wei Zhou;Liang Hu;Wen-tao Liu;Zhi-lan Yuan;Qing-Ping Li
糖尿病视网膜病变（diabetic retinopathy，DR）是糖尿病的一种严重并发症，亟待治疗。越来越多的证据表明，视网膜内的小胶质细胞炎症在DR中发挥着关键作用。小胶质细胞基质金属蛋白酶9（MMP-9）在与DR发展相关的血视网膜屏障（BRB）完整性的破坏中发挥着重要作用。MMP-9也被认为对于调节炎症反应很重要。芍药苷是一种单萜葡萄糖苷，对小胶质细胞具有有效的免疫调节作用。我们推测芍药苷能显著抑制高糖诱导的小胶质细胞MMP-9的活化，进而缓解DR。明胶酶谱法检测MMP-9的活性。通过蛋白质印迹分析和免疫荧光分析测量细胞信号传导。高糖可增加BV 2细胞MMP-9的活性，抑制HMGB 1、TLR 4、p38 MAPK和NF-κB可抑制高糖诱导的MMP-9活性。TLR 4抑制剂可降低高糖诱导的BV 2细胞p38 MAPK磷酸化水平。芍药苷诱导BV 2细胞中细胞因子信号传导抑制因子3（SOCS 3）表达并降低MMP-9活化。芍药苷对SOCS 3的作用可被TLR 4抑制剂阻断。在链脲佐菌素（STZ）诱导的糖尿病小鼠中，芍药苷诱导SOCS 3表达并降低MMP-9活化。芍药苷可抑制STZ诱导的IBA-1和IL-1β表达，降低STZ诱导的高血糖水平。结论：芍药苷通过上调SOCS 3抑制TLR 4/NF-κB通路，抑制高糖诱导的视网膜小胶质细胞MMP-9表达和炎症反应。
Diabetic retinopathy (DR) is a serious-threatening complication of diabetes and urgently needed to be treated. Evidence has accumulated indicating that microglia inflammation within the retina plays a critical role in DR. Microglial matrix metalloproteinase 9 (MMP-9) has an important role in the destruction of the integrity of the blood-retinal barrier (BRB) associated with the development of DR. MMP-9 was also considered important for regulating inflammatory responses. Paeoniflorin, a monoterpene glucoside, has a potent immunomodulatory effect on microglia. We hypothesized that paeoniflorin could significantly suppress microglial MMP-9 activation induced by high glucose and further relieve DR. BV2 cells were used to investigate the effects and mechanism of paeoniflorin. The activation of MMP-9 was measured by gelatin zymography. Cell signaling was measured by western blot assay and immunofluorescence assay. High glucose increased the activation of MMP-9 in BV2 cells, which was abolished by HMGB1, TLR4, p38 MAPK, and NF-κB inhibition. Phosphorylation of p38 MAPK induced by high glucose was decreased by TLR4 inhibition in BV2 cells. Paeoniflorin induced suppressor of cytokine signaling 3 (SOCS3) expression and reduced MMP-9 activation in BV2 cells. The effect of paeoniflorin on SOCS3 was abolished by the TLR4 inhibitor. In streptozotocin (STZ)-induced diabetes mice, paeoniflorin induced SOCS3 expression and reduced MMP-9 activation. Paeoniflorin suppressed STZ-induced IBA-1 and IL-1β expression and decreased STZ-induced high blood glucose level. In conclusion, paeoniflorin suppressed high glucose-induced retinal microglia MMP-9 expression and inflammatory response via inhibition of the TLR4/NF-κB pathway through upregulation of SOCS3 in diabetic retinopathy.