Paeoniflorin Suppressed High Glucose-Induced Retinal Microglia MMP-9 Expression and Inflammatory Response via Inhibition of TLR4/NF-[kappa]B Pathway Through Upregulation of SOCS3 in Diabetic Retinopathy

• Published in: Inflammation Vol. 40; no. 5; p. 1475
• Main Authors: Zhu, Su-hua, Liu, Bing-qian, Hao, Mao-juan, Fan, Yi-xin, Qian, Cheng, Teng, Peng, Zhou, Xiao-wei, Hu, Liang, Liu, Wen-tao, Yuan, Zhi-lan, Li, Qing-ping
• Format: Journal Article
• Language: English
• Published: New York Springer Nature B.V 01.10.2017
• Subjects: Diabetes; Diabetes mellitus; Diabetic retinopathy; Gelatin; Gelatinase B; Glucose; HMGB1 protein; Hyperglycemia; Immunofluorescence; Immunomodulation; Inflammation; Interleukin 1; MAP kinase; Matrix metalloproteinase; Metalloproteinase; Microglia; NF-κB protein; Phosphorylation; Retina; Retinopathy; Rodents; Signal transduction; SOCS-3 protein; Streptozocin; TLR4 protein; Toll-like receptors; Up-regulation
• ISSN: 0360-3997; 1573-2576
• DOI: 10.1007/s10753-017-0571-z

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-[kappa]B 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-1[beta] 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-[kappa]B pathway through upregulation of SOCS3 in diabetic retinopathy.