Abstract
Purpose : Dysregulated subretinal inflammation critically contributes to Age-related Macular Degeneration (AMD). Why the protective immune response becomes detrimental remains poorly defined. Single Ig IL-1-related receptor (SIGIRR) is an important negative regulator of the Toll-like receptor (TLR) and IL-1R signaling pathways and critically controls several innate immune responses. This study aims to understand the role of SIGIRR in age-induced subretinal inflammation and retinal degeneration.
Methods : The expression and location of SIGIRR in donated human eyes with and without AMD were examined by immunofluorescent staining. Young (3–4-month-old) and aged (12-13-month-old) SIGIRR deficient mice (Sigirr-/-) were used to evaluate the role of SIGIRR in age-related retinal inflammation and degeneration. Retinal thickness and electrophysiology were measured using Optical Coherence Tomography (OCT) and Electroretinogram (ERG). Retinal inflammation including inflammatory gene expression and immune cell infiltration was evaluated by RT-qPCR, RNA-Sequencing, and immunofluorescent staining.
Results : In AMD and healthy aged controls, SIGIRR was detected in Retinal Pigment Epithelium (RPE) and endothelial cells (n=3-5eyes). We did not detect any significant difference in the expression levels of SIGIRR in the retina and RPE. However, the expression of SIGIRR was significantly lower in neovascular AMD (nAMD) (Dunn’s multiple comparisons, P-value=0.0461). Photoreceptor layer thickness was unchanged throughout gene and age groups. ERG analysis revealed a significant reduction in a- and b-wave amplitude (µV), and implicit time (ms) in aged Sigirr-/- mice (n=6-18 eyes, unpaired t-test, P-value=0.01-0.001). Aged Sigirr-/- also had higher levels of inflammatory gene expressions, for instance, Ccl2 increases by 47 times in younger Sigirr-/- mice (n=5-6 eyes, Mann-Whitney test, P-value=0.0043) and have a much higher number of sub-retinal macrophage accumulation (Dunn’s multiple comparisons, P-value=0.0449).
Conclusions : Overall, our study suggests that Sigirr reduction or dysfunction accelerates age-induced retinal/subretinal inflammation and retinal functional decline.
Methods : The expression and location of SIGIRR in donated human eyes with and without AMD were examined by immunofluorescent staining. Young (3–4-month-old) and aged (12-13-month-old) SIGIRR deficient mice (Sigirr-/-) were used to evaluate the role of SIGIRR in age-related retinal inflammation and degeneration. Retinal thickness and electrophysiology were measured using Optical Coherence Tomography (OCT) and Electroretinogram (ERG). Retinal inflammation including inflammatory gene expression and immune cell infiltration was evaluated by RT-qPCR, RNA-Sequencing, and immunofluorescent staining.
Results : In AMD and healthy aged controls, SIGIRR was detected in Retinal Pigment Epithelium (RPE) and endothelial cells (n=3-5eyes). We did not detect any significant difference in the expression levels of SIGIRR in the retina and RPE. However, the expression of SIGIRR was significantly lower in neovascular AMD (nAMD) (Dunn’s multiple comparisons, P-value=0.0461). Photoreceptor layer thickness was unchanged throughout gene and age groups. ERG analysis revealed a significant reduction in a- and b-wave amplitude (µV), and implicit time (ms) in aged Sigirr-/- mice (n=6-18 eyes, unpaired t-test, P-value=0.01-0.001). Aged Sigirr-/- also had higher levels of inflammatory gene expressions, for instance, Ccl2 increases by 47 times in younger Sigirr-/- mice (n=5-6 eyes, Mann-Whitney test, P-value=0.0043) and have a much higher number of sub-retinal macrophage accumulation (Dunn’s multiple comparisons, P-value=0.0449).
Conclusions : Overall, our study suggests that Sigirr reduction or dysfunction accelerates age-induced retinal/subretinal inflammation and retinal functional decline.
| Original language | English |
|---|---|
| Article number | 560 |
| Journal | Investigative Opthalmology and Visual Science |
| Volume | 65 |
| Publication status | Published - 01 Jun 2024 |
| Event | Association for Research in Vision and Ophthalmology Annual Meeting 2024 - Seattle, United States Duration: 05 May 2024 → 09 May 2024 |