Role of single Ig IL-1-related receptor (SIGIRR/IL-1R8) in the immunopathogenesis of age-related macular degeneration (AMD)

Abstract

Purpose: Dysregulated subretinal inflammation critically contributes to Age-related Macular Degeneration (AMD). Why this protective immune response becomes detrimental remains poorly defined. Single Ig IL-1-related receptor (SIGIRR) is an important negative regulator of the Tol-like receptor (TLR) and IL-1R signalling pathways and critically controls a variety of innate immune responses. This study aims to understand the role of SlGIRR in age-induced subretinal inflammation and retinal degeneration. Methods: The expression and location of SIGIRR inhuman eyes with and without AMD were examined by immumostaining. Young (3-4-month-old) and aged (12-13-month-old) SIGIRR deficient mice (Sigirr-/-) were used to study the role of SIGIRR age-related retinal inflammation and degeneration. Retinal thickness and electrophysiology were measured using Optical Coherence Tomography (0CT) and Electroretinogram (ERG), respectively. Retinal inflammation, including inflammatory gene expression and immune cells infiltration, was evaluated by RT-qPCR, RNA Sequencing, and immunostaining. Results: In human AMD and healthy age-matched control samples, SIGIRR was detected in Retinal Pigment Epithelium (RPE) and endothelial cells. We did not detect any significant difference in the expression levels of SIGIRR in the retina and RPE (n=3-5 eyes). However, the expression of SIGIRR was significantly lower in the choroid of neovascular AMD (nAMD) samples. Retinal thickness did not differ between WT and Sigirr-/- mice in OCT. Aged Sigirr-/- mice displayed lower a-wave and b-wave amplitude (u) and longer implicit time (milliseconds); had increased expression of pro-inflammatory gene such as Ccl2 (increases by 47 aged Sigirr-/- compared to younger control mice) and a higher number of macrophage and microglial cells infiltrating the subretinal space. Conclusion: Altogether, our findings suggest that Sigirr deficiency increases age-induced retinal/subretinal inflammation and accelerates age-mediated declines in retinal functions.

Thesis is embargoed until 31 July 2030.

Date of Award	Jul 2025
Original language	English
Awarding Institution	Queen's University Belfast
Sponsors	Fight for Sight
Supervisor	Mei Chen (Supervisor), Heping Xu (Supervisor) & Yvonne Dombrowski (Supervisor)