Wnt inhibitory factor 1 inhibits glycolysis through the HIF1α/PFKFB3 signalling pathway to regulate macrophage polarization and alleviate diabetic retinopathy

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.

Wnt inhibitory factor 1; diabetic retinopathy; glycolysis; macrophage polarization.