Abstract
Purpose :
In premature infants, normal retinal vascular development is interrupted resulting in retinal ischemia and invasion of the vitreous by abnormal neovessels. In addition, vitreoretinal neovascularization can promote traction retinal detachment, leading to blindness. Laser ablation and anti-VEGF therapy are effective in preventing this pathology, but both can have adverse effects. New therapies are required to prevent the pathological neovascularization while promoting reparative growth of normal vessels. In retinopathy of prematurity (ROP), the retina is infiltrated by activated leukocytes and macrophages, and retinal microglial cells show phenotypic changes that have been implicated in the vascular pathology. Triggering receptor expressed on myeloid cells 1 (TREM-1), a recently discovered receptor of the immunoglobulin superfamily, activates neutrophils and monocytes/macrophages by signaling through the adapter protein DAP12. The TREM-1 gene is hypoxia-inducible and is involved in angiogenic signaling during tumor growth. The intention of this study is to evaluate the role of TREM-1 in pathological retinal neovascularization in a mouse model of oxygen-induced retinopathy (OIR).
Methods :
Studies were performed using OIR as a model for ROP. Wild-type neonatal mice were maintained in 75% oxygen from postnatal day P7 to P12 and in room air from P12 to P17. Mice with OIR received daily i.p. injections of novel TREM-1 peptide inhibitors or vehicle from P7 through P17. TREM-1 expression was measured by Western blotting and by immunofluorescence analysis of retinal flat mount sections double labeled with TREM-1 in combination with markers for macrophage/microglia (CD45/iba1). The vascular network was assayed by labeling with Isolectin B4
Results :
OIR induced a substantial increase in TREM-1 expression as shown by immunohistochemistry and Western blot. TREM-1 was localized specifically in areas of pathological vitreoretinal neovascularization, largely co-localizing with CD45 and to a lesser extent, iba1. TREM-1 blockade significantly reduced the area of vitreoretinal neovascularization (P<0.05).
Conclusions :
These results indicate that TREM-1 expressed on macrophage/microglia plays an important role in pathological retinal neovascularization and TREM-1 inhibition represents a novel strategy to treat ROP.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.