Deciphering the role of macrophages in subretinal fibrosis secondary to neovascular Age Related Macular Degeneration (nAMD)

Abstract

Neovascular Age-Related Macular Degeneration (nAMD) can display, in the late stage, the development of a fibrotic plaque in the subretinal space which we refer to as macular/subretinal fibrosis. Subretinal fibrosis is a major cause of anti-Vascular Endothelial Growth Factor (VEGF) drug resistance in nAMD. Unfortunately, it remains unpreventable and untreatable due to the incomplete understanding of the disease aetiology.

Over the years, evidence regarding the critical role of C-C Chemokine Receptor type 2 (CCR2) and CX3C Chemokine Receptor 1 (CX3CR1) subsets of macrophages in the progression of AMD have emerged. However, their role in the development of subretinal fibrosis remains unknown. This study aimed to understand how subretinal fibrosis develops secondary to choroidal neovascularisation (CNV) by investigating the role of CCR2+ infiltrating macrophages and CX3CR1+ macrophages/microglia.

In Chapter 3, we demonstrated that CX3CR1+ microglial cells were importantly involved in the development of CNV in the laser-induced CNV model. This was also confirmed in aged LysMCre-Socs3fl/flCx3cr1gfp/gfp (DKO) mice, which display microglial dysfunction and micro-retinopathy with age, indicating a potential role of microglia in retinal angiogenesis. In Chapter 4, we showed, using a mouse model of two-stage laser-induced subretinal fibrosis (TSLSF), that CX3CR1+ microglia depletion did not affect subretinal fibrosis progression. However, aged DKO mice displayed larger fibrovascular lesions suggesting that subretinal fibrosis may be supported by uncontrolled microglial activation.

Finally in Chapter 5, we demonstrated, using a mouse model of TSLSF, that both phagocyte subsets may play distinct roles in the progression of subretinal fibrosis as our results indicated that CCR2+ monocytes play a critical role in the development of the fibrovascular phenotype during the chronic stage of inflammation.

Overall, this study gives new insights in the understanding of the phagocyte infiltration dynamic in the subretinal space following injury and their implication towards the progression of subretinal fibrosis secondary to CNV.

Thesis is embargoed until 31 December 2027.

Date of Award	Dec 2023
Original language	English
Awarding Institution	Queen's University Belfast
Sponsors	Fight for Sight (Inc British Eye Research Foundation)
Supervisor	Heping Xu (Supervisor), Mei Chen (Supervisor) & Denise Fitzgerald (Supervisor)