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. 2018 Nov 18;11(11):1733-1740.
doi: 10.18240/ijo.2018.11.01. eCollection 2018.

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

Lin Li  1   2 , Yan-Ling Dong  2 , Ting Liu  2 , Dan Luo  2 , Chao Wei  2 , Wei-Yun Shi  2
Affiliations

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

Lin Li et al. Int J Ophthalmol. .

Abstract

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 real-time reverse transcription polymerase chain reaction (qRT-PCR) 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.

Keywords: Mooren's ulcer; nuclear factor-κB; pathogenesis; succinate receptor.

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Figures

Figure 1
Figure 1. Ocular surface of patients with Mooren's ulcer
A: The representative slit lamp photography; B: The representative RTvue OCT image.
Figure 2
Figure 2. Increased expression of succinate receptor GPR91 in the biopsies of MU patients
A: IHC staining showed the elevated expression of GPR91 in the cornea and conjunctiva (magnification ×400); B: Quantitative analysis of transcriptional expression of GPR91 showed significantly elevated expression in the MU samples (aP<0.05 vs control, n=3).
Figure 3
Figure 3. Succinate promoted the expression of inflammatory cytokines and MMP-13 through GPR91 in PBMCs
A: Quantitative analysis of mRNA expression of IL-1β, NLRP3, VEGF-A and MMP-13 in PBMCs treated with LPS, succinate and JSH-23 for 12h; B: Western blot analysis of IL-1β, NLRP3, VEGF-A and MMP-13 in lysates of PBMCs treated with LPS, succinate and JSH-23 for 12h; C: The concentrations of IL-1β in supernatants of PBMCs for 12h. aP<0.05; bP<0.01.
Figure 4
Figure 4. Ligation of GPR91 with succinate significantly augmented NF-κB activity in LPS-stimulated PBMCs
A: Western blot analysis of p-p65 and p65 in lysates of PBMCs after treatment with LPS, succinate and JSH-23 for 1h; B: Quantification of p-p65 in stimulated cells relative to that in unstimulated cells as in A. bP<0.01.
Figure 5
Figure 5. Analyses of IL-1β, MMP-13, VEGF-A and p65 expressions in the MU samples
Analysis of IL-1β (A), MMP-13 (B), VEGF-A (C) and p65 (D) expressions in the cornea and conjunctiva by IHC (magnification ×400); E: Analyzing the transcriptional expression of IL-1β and VEGF-A in the samples of patients with MU (n=3). aP<0.05, bP<0.01.
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