Essential Contribution of Macrophage Tie2 Signalling in a Murine Model of Laser-Induced Choroidal Neovascularization

Xue Yin,Lei Chen,Weiming Liu,Wei Xia,Gaoqin Liu,Bingyu Zhang,Chi Ren,Peirong Lu,Xuefei Zhu

doi:10.1038/s41598-020-66580-y

Abstract

Wet age-related macular degeneration (AMD), which can cause progressive blindness, is characterised by choroid neovascularization (CNV) in the macular area. Although close attention has been paid to AMD, and anti-vascular endothelial growth factor (VEGF) drugs are available, its complex pathogenesis is still elusive. Tie2-expressing macrophages (TEMs) have been found to promote angiogenesis in remodel tissues and tumours. This study aimed to elucidate the role of macrophage Tie2 signalling in laser-induced CNV (LCNV). We observed that TEMs were responsible for the severity of CNV. Mechanistically, TEM deletion resulted in impaired LCNV due to the suppression of inflammatory angiogenesis and the promotion of apoptosis. We also observed that TEMs prevented apoptosis of b.End3 cells, but promoted their migration, proliferation and tube formation via VEGF, extracellular signal-regulated kinase (ERK) and v-akt murine thymoma viral oncogene (AKT)-dependent signalling pathways. The flow cytometry results comparing dry AMD patients and healthy controls with wet AMD patients showed that the percentage of Tie2+CD14+ cells was higher in the wet AMD patients’ peripheral blood. This study demonstrates that Tie2 expression by macrophages intensifies CNV in LCNV murine models, thereby proposing an additional intervention option to inhibit CNV.

Highlights

Tie2-expressing macrophages (TEMs) are a subpopulation of macrophages
Accumulation of intra-choroidal TEMs increased during laser-induced CNV (LCNV)
To study the role of TEMs in LCNV, laser injury was induced to the choroid plexus of mice

Summary

Introduction

Tie2-expressing macrophages (TEMs) are a subpopulation of macrophages. Their presence and phenotype have been confirmed in human blood[8]. TEMs have been found to promote angiogenesis in remodel tissues and tumours[9]. Deletion of TEMs was reported to inhibit angiogenesis in limb ischemia, hepatocellular carcinoma and tumour relapse[10,11,12]. Researchers have reported that, potentially, increased recruitment of TEMs plays a role in enhanced neovascularization[13,14]. Macrophage Tie2-signal mediated-autophagy plays a critical role in LCNV14. The actual role of TEMs in AMD is still unclear.

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