Related Experiment Video
Updated: Aug 31, 2025
Author Spotlight: Understanding Retinal Vessel Resilience and Disease Progression
Published on: January 12, 2024
Kdm6a deficiency in microglia/macrophages epigenetically silences Lcn2 expression and reduces photoreceptor
Yanjun Wen1, Xin Chen2, Huazhang Feng3
1Department of Ophthalmology, Eye & ENT Hospital, Shanghai Medical College, Fudan University, Shanghai 200031, China; Department of Ophthalmology, Shanghai Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China; NHC Key Laboratory of Myopia (Fudan University), Key Laboratory of Myopia, Chinese Academy of Medical Sciences, Shanghai Key Laboratory of Visual Impairment and Restoration (Fudan University), Shanghai 200032, China.
Abstract:
Diabetic retinopathy (DR) is one of the leading causes of severe visual impairment worldwide. However, the role of adaptive immune inflammation driven by microglia/macrophages in DR is not yet well elucidated. Kdm6a is a histone demethylase that removes the trimethyl groups of histones H3K27 and plays important biological roles in activating target genes. To elucidate the role of Kdm6a in microglia/macrophages in diabetic retinas, we established diabetic animal models with conditional knockout mice to investigate the impacts of Kdm6a deficiency. The RNA-seq analysis, mass spectrum examination, immunohistochemistry and detection of enzyme activities were used to elucidate the effect of Kdm6a deletion on gene transcription in microglia/macrophages. The expression of Kdm6a was increased in the retinas of diabetic mice compared to the control group. Loss of Kdm6a in microglia/macrophages ameliorated the diabetes-induced retinal thickness decrease, inflammation, and visual impairment. Kdm6a in microglia/macrophages regulated Lcn2 expression in a demethylase activity-dependent manner and inhibited glycolysis progression in photoreceptor cells through Lcn2. These results suggest that Kdm6a in microglia/macrophages aggravated diabetic retinopathy by promoting the expression of Lcn2 and impairing glycolysis progression in photoreceptor cells.
Insights
Kdm6a in immune cells worsens diabetic retinopathy (DR) by increasing Lcn2 and hindering photoreceptor glycolysis. Removing Kdm6a in these cells improves vision and reduces retinal damage in diabetic models.
Area of Science:
- Immunology
- Ophthalmology
- Epigenetics
Background:
- Diabetic retinopathy (DR) is a major cause of vision loss.
- The role of microglia/macrophages in DR-related inflammation is not fully understood.
- Kdm6a is an epigenetic regulator involved in gene activation.
Purpose of the Study:
- To investigate the role of Kdm6a in microglia/macrophages in diabetic retinopathy.
- To understand how Kdm6a influences retinal inflammation and visual function in diabetes.
Main Methods:
- Diabetic mouse models with conditional Kdm6a knockout in microglia/macrophages.
- RNA-sequencing, mass spectrometry, immunohistochemistry, and enzyme activity assays.
- Assessment of retinal thickness, inflammation, and visual impairment.
Main Results:
- Kdm6a expression increased in diabetic mouse retinas.
- Kdm6a deficiency in microglia/macrophages ameliorated retinal thinning, inflammation, and visual impairment.
- Kdm6a regulated Lcn2 expression and inhibited photoreceptor glycolysis.
Conclusions:
- Kdm6a in microglia/macrophages exacerbates diabetic retinopathy.
- Targeting Kdm6a may offer a therapeutic strategy for DR by modulating Lcn2 and glycolysis.
