Abstract
Necrosis is a form of cell death that results in rupture of the plasma membrane and the release of cellular contents, and it can give rise to sterile inflammation in the retina and other tissues. The secretion of vascular endothelial growth factor (VEGF) by retinal pigment epithelial (RPE) cells contributes to retinal homeostasis as well as to pathological angiogenesis. We have now examined the effect of a necrotic cell lysate prepared from human RPE cells (NLR) on the release of VEGF by healthy RPE cells. We found that NLR markedly increased the release of VEGF from RPE cells and that this effect was attenuated by nintedanib, a multiple receptor tyrosine kinase inhibitor, whereas it was unaffected by inhibitors of NF-κB signaling or of caspase-1. NLR also induced the phosphorylation of extracellular signal–regulated kinase (Erk) and signal transducer and activator of transcription 3 (Stat3) in a manner sensitive to inhibition by nintedanib, although inhibitors of Erk and Stat3 signaling pathways did not affect NLR-induced VEGF secretion. In addition, nintedanib attenuated the development of choroidal neovascularization in mice. Our results have thus shown that a necrotic lysate of RPE cells induced VEGF secretion from healthy RPE cells and that this effect was mediated by receptor tyrosine kinase signaling. They therefore suggest that VEGF secretion by healthy RPE cells is a potential therapeutic target for retinal diseases associated with sterile inflammation and pathological angiogenesis.
Highlights
Inflammation is an initial response of organs or tissues to external or internal factors and contributes to homeostasis
To investigate whether receptor tyrosine kinases (RTKs) signaling might contribute to necrotic cell lysate of ARPE-19 cells (NLR)-induced vascular endothelial growth factor (VEGF) secretion from retinal pigment epithelial (RPE) cells, we examined the effect of a multiple RTK inhibitor
To examine the pathological activation of RPE cells in sterile inflammation, which is associated with several retinal diseases including age-related macular degeneration (AMD) and diabetic retinopathy [3, 4], we investigated the effects of a necrotic cell lysate derived from RPE cells on VEGF secretion from healthy RPE cells
Summary
Inflammation is an initial response of organs or tissues to external or internal factors and contributes to homeostasis. The cellular contents released from damaged or necrotic cells can serve as a source of danger signals and play a role in the pathogenesis of various diseases associated with activation of the innate immune system [1, 2]. Pathogen-free inflammation induced by such cell damage or necrosis (sterile inflammation) is thought to contribute to several retinal diseases including diabetic retinopathy and age-related macular degeneration (AMD) [3, 4]. Inhibition by nintedanib of VEGF secretion from RPE cells induced by a necrotic cell lysate [5, 6] from various cell types in response to the activation of inflammasome-dependent or -independent signaling pathways including that mediated by nuclear factor (NF)–κB [7]. Focal adhesion–dependent signaling has been implicated in sterile inflammation [8], as has signaling triggered by various nonimmune receptors including G protein–coupled receptors and receptor tyrosine kinases (RTKs) [9, 10]
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