Twarog, Michael, Schustak, Joshua, Xu, YongYao, Coble, Matthew, Dolan, Katie, Esterberg, Robert, Huang, Qian, Saint-Geniez, Magali and Bao, Yi (2023) TNFα induced by DNA-sensing in macrophage compromises retinal pigment epithelial (RPE) barrier function. Scientific reports, 13 (1). p. 14451. ISSN 2045-2322

Abstract

Increasing evidence suggests that chronic inflammation plays an important role in the pathogenesis of age-related macular degeneration (AMD); however, the precise pathogenic stressors and sensors, and their impact on disease progression remain unclear. Several studies have demonstrated that type I interferon (IFN) response is activated in the retinal pigment epithelium (RPE) of AMD patients. Previously, we demonstrated that human RPE cells can induce RNA-mediated type I IFN responses through RIG-I, however, they are unable to directly sense and respond to DNA. In this study, we utilized a co-culture system combining primary human macrophage and iPS-derived RPE to study how each cell type responds to nucleic acids challenges and their effect on RPE barrier function in a homotypic and heterotypic manner. We find that DNA-induced macrophage activation activates RPE IFN response and compromises their barrier function via tight-junctions remodeling. Investigation of the secreted cytokine(s) responsible for RPE dysfunction following DNA-induced macrophages activation indicates that neutralization of macrophage-secreted TNFα, but not IFNβ, is sufficient to rescue RPE morphology and barrier function. Our data reveal a novel mechanism of intercellular communication by which DNA induces RPE dysfunction via macrophage-secreted TNFa, highlighting the complexity and potential pathological relevance of RPE and macrophages interactions.

Item Type:	Article
Keywords:	Retinal Pigmented Epithelial (RPE), macrophage, nucleic acid sensing, cytokines, TNFα
Date Deposited:	23 Sep 2023 00:45
Last Modified:	23 Sep 2023 00:45
URI:	https://oak.novartis.com/id/eprint/51005