Monocyte/macrophage-derived IL-15 activates STAT5 to trigger the EFNA1/NCOA2-positive feedback loop, facilitating...

Diabetic retinopathy (DR) is of the most prevalent complications among diabetic patients. The potential role of interleukin 15 (IL-15) in modulating immune cell function and angiogenesis has drawn considerable attention. Nevertheless, the precise mechanism through which IL-15 operates in DR remains elusive.

The GSE185011 and GSE221521 data sets were harnessed to screen for upregulated genes in the blood and peripheral blood mononuclear cells (PBMCs) of patients with DR. The GSE236333 and GSE179568 data sets were used to identify upregulated genes in retinal tissues. In the clinical investigation, IL-15 was detected in T and B lymphocytes, as well as in monocytes/macrophages within the PBMCs of patients. Human retinal microvascular endothelial cells and human umbilical vein endothelial cells were either cocultured with the monocyte/macrophage cell line THP-1 under high-glucose (HG) conditions or treated with IL-15.

Among the three cell types in PBMCs, monocytes/macrophages exhibited the most substantial upregulation of IL-15 under HG conditions. In vitro, IL-15 secreted by THP-1 cells augmented the STAT5 in human retinal microvascular endothelial cells and human umbilical vein endothelial cells, thereby enhancing their angiogenic potential. Inhibition of STAT5 expression counteracted the proangiogenic effect of IL-15 on endothelial cells and diminished the expression of epithelial cell adhesion molecule 1 (EFNA1). After the knockdown of nuclear receptor coactivator 2 (NCOA2), the binding affinity of STAT5 to the EFNA1 gene promoter was significantly attenuated, and the influence of IL-15 on EFNA1 expression and angiogenesis was markedly reduced. Intriguingly, knockdown of either EFNA1 or NCOA2 led to a concurrent decrease in the expression of both genes in endothelial cells, suggesting a positive feedback regulatory loop between them.

IL-15 secreted by monocytes/macrophages activates STAT5, which in turn induces a positive feedback regulation of the EFNA1/NCOA2 axis, ultimately promoting retinal angiogenesis under HG conditions.