Abstract
Purpose :
Choroidal neovascularization (CNV), an advanced form of age-related-macular-degeneration (AMD), is associated with gradual loss of choroidal integrity. However, the molecular mechanisms of CNV initiation and the loss of choroidal integrity remain unexplored. Signaling molecules that help maintain local immune cell populations and regulate local inflammation are suggested to contribute to CNV. Interferon regulatory factor 5 (IRF5) is a transcription factor known for modulation of inflammation and for promoting macrophage subtype polarization between M1 (proinflammatory) and M2 (proangiogenic). Here, we aim to dissect the function of IRF5 in CNV development by characterizing a IRF5 knockout (IRF5null) mouse model.
Methods :
Loss of IRF5 expression in RPE/choroid was verified by qRT-PCR and immunohistochemistry with antibody against IRF5. Ocular structures were evaluated live using optical coherence tomography (OCT) and fluorescein angiography, and histologically using light and confocal microscopy. Immune cell populations were characterized by flow cytometry and immunohistochemistry with lineage specific and activation markers, including CD11b, CD11c, F4/80, CD86, CD206, CD14, MHCII, Ly6c. Retina physiology was studied by electroretinography (ERG).
Results :
IRF5 null homozygous eyes displayed an increase in the number of immature macrophages. Phenotypically, IRF5 null mice showed normal gross anatomical structure at birth. By 9 months of age, choroidal /RPE morphological defects include overgrowth of new choroidal vessels that invade sub-RPE/Bruch’s membrane, degeneration of RPE overlying CNV, and overt presence of migratory cells, presumably phagocytes, in the subretinal space. These changes were concomitant with a reduction in the response amplitudes in the a- and b- waves of ERG.
Conclusions :
Loss of IRF5 is sufficient to induce CNV in the eye and compromise choroid/RPE/retina homeostasis. These findings indicate an important role for the IRF5 in controlling immune regulation in the posterior part of the eye. IRF5 null eyes can serve as a model for studying early events in AMD pathogenesis.
This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.