Flt3 Regulation in the Mononuclear Phagocyte System Promotes Ocular Neovascularization

Yushuo Gao,Anna M Demetriades,Qing Lu,Bing Xie,Yanji Zhu,Jikui Shen,Yisheng Zhong,Yujuan Cai,Xi Shen

doi:10.1155/2018/2518568

Abstract

Fms-like tyrosine kinase 3 (Flt3), a tyrosine kinase receptor expressed in CD34+ hematopoietic stem/progenitor cells, is important for both normal myeloid and lymphoid differentiation. It has been implicated in mice and humans for potential multilineage differentiation. We found that mice deficient in Flt3 or mice that received an Flt3 inhibitor (AC220) showed significantly reduced areas of ischemia-induced retinal neovascularization (RNV) and laser-induced choroidal NV (CNV) (P < 0.05). Increased Flt3 expression at the protein level was detected in retinas of oxygen-induced retinopathy (OIR) mice at P15 and P18 during retinal NV (RNV) progression. We subsequently found that macrophages (Mphi) polarization was regulated at the site of CNV in Flt3-deficient mice. Flow cytometry analysis demonstrated that Flt3 deficiency shifted Mphi polarization towards an M2 phenotype during RNV with significant reduction in M1 cytokine expression when compared to the wild-type controls (P < 0.05). Based on the above findings, we concluded that Flt3 inhibition alleviated ocular NV by promoting a Mphi polarization shift towards the M2 phenotype. Therapies targeting Flt3 may provide a new approach for the treatment of ocular NV.

Highlights

Age-related macular degeneration (AMD) represents an ailment whose incidence increases with age and is a leading cause of vision problems in older adults worldwide, affecting approximately 9% of the global population [1,2,3]
Retinas from P18 mice after oxygen-induced ischemic retinopathy displayed increased Fms-like tyrosine kinase 3 (Flt3) staining in the inner retina with colocalization of GSA-Lectin on the retinal surface in new vessels (Figure 1(B))
Retina specimens from P21 transgenic animals overexpressing vascular endothelial growth factor (VEGF) in photoreceptors showed Flt3 expression in inner and intermediate layers with a close association with GSALectin (Figure 1(C))

Summary

Introduction

Age-related macular degeneration (AMD) represents an ailment whose incidence increases with age and is a leading cause of vision problems in older adults worldwide, affecting approximately 9% of the global population [1,2,3]. Neovascular AMD progresses rapidly, resulting in 80%–90% of cases with severe vision loss [1]. Angiogenesis and neovascularization have been studied to a great extent, allowing the development of antiangiogenic products to treat malignancies as well as ocular diseases [5]. Angiogenesis plays a critical role in development, reproduction, and repair; it involves degeneration of the vascular basement membrane, which is normally continuous, and the activation of quiescent endothelial cells (ECs) [6,7,8]. There is an increasing number of patients benefiting from angiogenesis inhibitors such as vascular endothelial growth factor (VEGF), reduced efficacy and resistance continue to challenge the way we treat the disease [11,12,13,14]. Several reports have revealed novel molecular mechanisms that provide unique avenues for the improvement of antiangiogenic strategies [14,15,16]

Methods

Results

Conclusion