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Wnt inhibitory factor 1 inhibits glycolysis through the HIF1α/PFKFB3 signalling pathway to regulate macrophage
Meng-Jiao Wang1, Xiao-Yan Zhao1, Guo-Hua Lu1
1The Second People's Hospital of Changzhou, Nanjing Medical University, Changzhou, China.
Aims:
Diabetic retinopathy (DR) has been associated with aberrant Wnt inhibitory factor 1 (WIF1) expression and dysregulated glycolysis. However, no study has yet reported how WIF1 links glycolysis to macrophage polarization and thus influences DR progression. Therefore, the objective of this study was to investigate the regulation of macrophage polarization and glucose metabolism by WIF1 in DR and to determine its impact on DR progression.
Methods:
To investigate the role of WIF1, a streptozotocin (STZ)-induced diabetic mouse model was utilized. High glucose was used to treat THP-1-derived macrophages, with or without WIF1 overexpression. The involvement of the HIF1α/PFKFB3 pathway was probed using the HIF1α stabilizer DMOG and the PFKFB3 inhibitor meclizine. Key analyses included retinal histology (H&E staining), macrophage phenotyping (flow cytometry for M1/M2 markers) and measurement of glycolytic activity (lactate production) and related gene expression (RT-qPCR and western blot).
Results:
The weight loss, elevated blood glucose levels, increased plasma glycated haemoglobin ratio, decreased WIF1 expression, increased glycolysis and elevated number of M1 macrophages were observed in DR mice. HE staining revealed significant retinal tissue damage in DR mice. The pathological changes were mitigated by WIF1 overexpression. It has been demonstrated that elevated glucose levels can induce M1 polarization of macrophages, resulting in increased glycolysis, promotion of the inflammatory response and lactate accumulation. In addition, these effects have been shown to be attenuated by WIF1 overexpression. Treatment with DMOG and meclizine served to attenuate the effects of WIF1 overexpression, as evidenced by the increased expression of HIF-1α/PFKFB3, and promoted glycolysis and the M1 polarization of macrophages.
Conclusion:
Overexpression of WIF1 inhibits glycolysis via the HIF1α/PFKFB3 signalling pathway, thereby modulating the polarization of macrophages and alleviating the progression of DR. These findings suggest that WIF1 could be a promising therapeutic target for DR.
Insights
Wnt inhibitory factor 1 (WIF1) reduces glycolysis and M1 macrophage polarization, mitigating diabetic retinopathy (DR) progression. WIF1 targets the HIF1α/PFKFB3 pathway, offering a potential therapeutic strategy for DR.
Area of Science:
- Ophthalmology
- Immunology
- Metabolism
Background:
- Diabetic retinopathy (DR) is linked to abnormal Wnt inhibitory factor 1 (WIF1) expression and altered glycolysis.
- The connection between WIF1, glycolysis, and macrophage polarization in DR pathogenesis remains unclear.
Purpose of the Study:
- To investigate how WIF1 regulates macrophage polarization and glucose metabolism in diabetic retinopathy (DR).
- To determine the impact of WIF1 on DR progression.
Main Methods:
- Utilized a streptozotocin-induced diabetic mouse model and high glucose-treated THP-1 macrophages.
- Investigated the HIF1α/PFKFB3 pathway using DMOG and meclizine.
- Assessed retinal histology, macrophage phenotype, glycolytic activity, and gene expression.
Main Results:
- DR mice exhibited decreased WIF1, increased glycolysis, and elevated M1 macrophages, alongside retinal damage.
- WIF1 overexpression mitigated DR pathology, reduced M1 polarization, and decreased glycolysis.
- DMOG and meclizine treatments counteracted WIF1's protective effects, promoting M1 polarization and glycolysis.
Conclusions:
- WIF1 overexpression inhibits glycolysis via the HIF1α/PFKFB3 pathway, modulating macrophage polarization and alleviating DR progression.
- WIF1 represents a potential therapeutic target for managing diabetic retinopathy.
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