Metabolic adaptation controls the divergent polarization of macrophage that drives retinal scarring

Abstract

Purpose : Retinal scarring is the end-stage condition of multiple fundus diseases associated with abnormal wound healing and neovascularization. However, there are currently no therapies that can prevent or reverse retinal fibrosis, leading to catastrophic visual loss. Due to the flawed animal model and inaccessible human sample, the cellular origin of scar-forming cells in the retina remains elusive. The novel role of myeloid cells was previously reported to participate in the formation of retinal scarring. The current study aimed to explore the mechanism by which myeloid cells contribute to retinal scarring and add a novel immunometabolic avenue to antifibrotic therapy.

Methods : We profiled the single-cell transcriptomes of human retinal fibrotic tissues including fibrovascular membrane from proliferative diabetic retinopathy (PDR) and epiretinal membrane from proliferative vitreoretinopathy (PVR). We used functions from Seurat for dimension-reduction and clustering. Bioinformatics analysis including gene ontology enrichment analysis, pathway activity analysis, heatmap analysis and pseudotime analysis to identify the origin, classification, function and metabolic features of myeloid cells. We established two murine models of retinal scarring by intravitreal injection of cells and laser burring of fundus in vivo and primary peritoneal macrophages culture in vitro to validate our hypothesis. Two-tailed Student's t-test was used for statistical analysis.

Results : Our single-cell transcriptomics analysis revealed the predominant presence of scar-associated macrophage (SAM) in the retinal scar tissues and further identified two macrophage polarities with distinct but synergistic functions in tissue remodeling. Furthermore, the two macrophage subpopulations coexisted in the localized hypoxia via lactate-mediated symbiotic metabolism. Pharmacologic blockade of lactate oxidation specifically diverted the polarization of SAM and significantly reverse retinal scarring in different murine models of retinal diseases.

Conclusions : We identified two polarities of retinal SAM differed in terms of localization and function, which were defined by distinct metabolic adaptations to hypoxia. Manipulating the macrophage metabolism fine-tuned the fate outcome of SAM and the progression of retinal scarring, indicating a potential therapeutic target to reverse retinal scar.

This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.