Kdm6a deficiency in microglia/macrophages epigenetically silences Lcn2 expression and reduces photoreceptor dysfunction in diabetic retinopathy

Yanjun Wen; Xin Chen; Huazhang Feng; Xu Wang; Xiaoli Kang; Peiquan Zhao; Chen Zhao; Yan Wei

doi:10.1016/j.metabol.2022.155293

Kdm6a deficiency in microglia/macrophages epigenetically silences Lcn2 expression and reduces photoreceptor dysfunction in diabetic retinopathy

Metabolism. 2022 Nov:136:155293. doi: 10.1016/j.metabol.2022.155293. Epub 2022 Aug 19.

Authors

Yanjun Wen¹, Xin Chen², Huazhang Feng³, Xu Wang², Xiaoli Kang⁴, Peiquan Zhao⁴, Chen Zhao⁵, Yan Wei⁶

Affiliations

¹ Department 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.
² Department of Oral and Maxillofacial-Head and Neck Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China; National Clinical Research Center for Oral Disease, Shanghai, 200011, China; Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, Shanghai, 200011, China.
³ Department 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.
⁴ Department of Ophthalmology, Shanghai Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China.
⁵ Department of Ophthalmology, Eye & ENT Hospital, Shanghai Medical College, Fudan University, Shanghai 200031, 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.
⁶ Department of Ophthalmology, Eye & ENT Hospital, Shanghai Medical College, Fudan University, Shanghai 200031, 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. Electronic address: yan.wei@fdeent.org.

PMID: 35995279
DOI: 10.1016/j.metabol.2022.155293

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.

Keywords: Diabetic retinopathy; Glycolysis; Kdm6a; Lcn2; Macrophage; Microglia.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Diabetes Mellitus, Experimental* / complications
Diabetes Mellitus, Experimental* / genetics
Diabetes Mellitus, Experimental* / metabolism
Diabetic Retinopathy* / genetics
Histone Demethylases* / genetics
Histones / metabolism
Inflammation / genetics
Inflammation / metabolism
Lipocalin-2* / genetics
Lipocalin-2* / metabolism
Macrophages / metabolism
Mice
Mice, Knockout
Microglia / metabolism
Photoreceptor Cells / metabolism

Substances

Histones
Lipocalin-2
Lcn2 protein, mouse
Histone Demethylases
Utx protein, mouse