Work

Oxidative stress-induced proinflammatory secretion from retinal pigment epithelium disrupts NAD+ metabolism via CD38 on macrophages leading to immune microenvironment dysregulation

Year: 2025

Type: article

Abstract: Oxidative damage at the retinochoroidal interface manifests as retinal pigment epithelium (RPE) damage and subretinal macrophage accumulation. This study aimed to explore the role of oxidative stress (OS) in the RPE cells affecting metabolic reprogramming and associated molecular mechanisms in macrophages. In vivo, RPE damage models in C57BL/6J mice were generated via the intraperitoneal injection of sodium iodate (SI). Following oral gavage intervention with or without the cluster of differentiation 38 (CD38) inhibitor 78c, macrophage infiltration and polarization, inflammatory markers, the NAD + content, and the structure of Bruch’s membrane (BrM) were observed in this model. In vitro, macrophages were co-cultured with OS-induced RPE. Comprehensive transcriptomics, targeted metabolomics, functional assays, and molecular mechanism studies were employed to clarify key NAD + metabolic enzyme expression changes, metabolite alterations, macrophage cellular processes and intracellular molecular changes. In the RPE damage mouse model, the proportion of circulating non-tissue-resident infiltrating CD38 + macrophages significantly increased, with these cells primarily accumulating in the subchoroidal space, accompanied by elevated inflammatory marker levels and disrupted structure, which were reversed by 78c gavage intervention. In vitro, after co-cultured with OS-induced RPE, macrophages exhibited proinflammatory changes and intracellular NAD + depletion, along with dysregulated extracellular matrix (ECM) interactions. Molecular mechanism experiments revealed that CD38 upregulation inhibited fibronectin expression via the NAD + /PARP1/FOS pathway, which led to a decrease in migration and adhesion functions. OS in the RPE drives metabolic reprogramming in macrophages via cytokine secretion, altering their transcriptional profiles and cellular functions. Our study established CD38 as a promising therapeutic target for modulating macrophage-driven pathology in OS-associated ocular disorders. • Oxidative stressed retinal pigment epithelium recruits peripheral CD38 + macrophages • CD38 upregulation caused macrophage-extracellular matrix interaction dysfunction • CD38-dependent NAD + depletion suppressed fibronectin expression • CD38 inhibition suppressed inflammation and restored Bruch’s membrane integrity

Source: Free Radical Biology and Medicine

DOI: 10.1016/j.freeradbiomed.2025.11.041