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Increased succinate receptor GPR91 involved in the pathogenesis of Mooren's ulcer

查看全文 作　　者：Lin [1,2]Li;Yan-Ling [2]Dong;Ting [2]Liu;Dan [2]Luo;Chao [2]Wei;Wei-Yun [2]Shi 高影响力作者 机构地区：[1]School of Medicine and Life Sciences, University of JinanShandong Academy of Medical Sciences;[2]State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Shandong Eye Institute,Shandong Academy of Medical Sciences高影响力机构 出　　处：《International Journal of Ophthalmology(English edition)》索引2018年第11卷第11期,共8页高影响力期刊 基　　金：Supported by National Natural Science Foundation of China (No.81530027; No.81500767; No.81570821);Natural Science Foundation of Shandong Province (No. ZR2018PH020; No.ZR2015YL037);the Innovation Project of Shandong Academy of Medical Sciences 摘　　要：AIM: To investigate the expression of succinate receptor GPR91 and its pathogenic roles in Mooren's ulcer(MU).METHODS: Biopsy specimens were obtained from 7 patients with MU and 6 healthy donors. The expression of GPR91 in MU tissues was evaluated using quantitative realtime reverse transcription polymerase chain reaction(qRTPCR) and immunohistochemistry(IHC). Succinate was used to activate GPR91 signaling, and the effect of GPR91 on the expression of interleukin-1β(IL-1β), NLRP3, vascular endothelial growth factor(VEGF) and matrix metalloproteinase-13(MMP-13) in human peripheral blood mononuclear cells(PBMCs) was determined. The influence of GPR91 on the nuclear factor-κB(NF-κB) signaling in PBMCs was investigated by detecting the phosphorylation of p65. Moreover, the expression of IL-1β, VEGF, MMP-13 and phosphorylated p65(p-p65) in the tissues of MU was examined by qRT-PCR or IHC.RESULTS: GPR91 mRNA expression showed a higher level in the MU group than in the healthy control group. IHC analysis also revealed that the expression of GPR91 was elevated in patients with MU compared with healthy controls. Moreover, ligation of GPR91 with succinate promoted the lipopolysaccharide-induced production of NLRP3, IL-1β, VEGF and MMP-13 in PBMCs through increased phosphorylation of p65. Pharmacological inhibition of the NF-κB signaling reversed GPR91 induced production of NLRP3, IL-1β, VEGF and MMP-13. These findings, coupled with the elevated amounts of IL-1β, VEGF, MMP-13 and p-p65 observed in the MU biopsies, constituted a rational basis for the involvement of GPR91 in the pathogenesis of MU.CONCLUSION: This study indicates the increased succinate receptor GPR91 in conjunctival or corneal tissues is involved in the pathogenesis of MU through elevated NF-κB activity, which may provide a new therapeutic target for MU. 关 键 词：succinate receptor Mooren’s ulcer nuclear factor-κB PATHOGENESIS
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