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

Abstract

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 the aqueous humor and found that HDGF was 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 enzyme-linked immunosorbent assays, quantitative reverse transcription-PCR, Western blotting, 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 neutralization of HDGF suppressed these effects caused by high glucose. Furthermore, the HDGF receptor nucleolin was overexpressed in microglia under high glucose stimulation. Therefore, blocking HDGF from Müller cells in DR reduced the excessive inflammatory response in microglia, highlighting HDGF as a potential therapeutic target.

Keywords

hepatoma-derived growth factor / diabetic retinopathy / microglia / Müller cell / inflammatory response / integrin beta 2

Funding

We thank all donors for their donation. This study was supported by National Natural Science Foundation of China (Grant No. 81900873 to A.Q.), the Jiangsu Provincial Key Research and Development Programme-social development (Grant No. BE2023777 to W.Z.), the Key Medical Research Project of Jiangsu Commission of Health (Grant No. H2022185 to W.Z.), and the Clinical Capacity Enhancement Project of Jiangsu Province Hospital (Grant No. JSPH-MB-2023-18 to W.Z.).

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