HDGF derived from Müller cells enhances the activation of microglia in diabetic retinopathy

Diabetic retinopathy (DR), a common complication of diabetes, is characterized by retinal angiogenesis and inflammation. The role of hepatoma-derived growth factor (HDGF) in mediating inflammation during DR remains unclear. We measured HDGF levels in aqueous humor and found that HDGF increased in DR but decreased after anti-angiogenesis treatment. Using public single-cell RNA sequencing datasets, we found that elevated HDGF in DR was mainly produced by Müller cells and targeted microglia. Additionally, integrin beta 2 (Itgb2), a target gene of HDGF that induces microglial activation, was significantly upregulated in DR. To verify these results, we performed ELISA, qPCR, western blot, and fluorescence immunostaining in cultured Müller and microglial cells treated with HDGF or anti-HDGF, as well as in DR mice receiving intravitreal injections of HDGF or its antibody. Exogenous HDGF further promoted microglial activation, migration, and secretion of pro-inflammatory cytokines, while neutralizing HDGF suppressed these effects caused by high glucose. Furthermore, the HDGF receptor nucleolin (NCL) was overexpressed in microglia under high glucose stimulation. Therefore, blocking HDGF from Müller cells in DR reduced the excessive inflammatory response of microglia, highlighting HDGF as a potential therapeutic target.