Abstract
BackgroundChemokine signalling is required for the homing of leukocytes during retinal inflammation, and is associated with pathogenesis of diseases such as age-related macular degeneration (AMD). Here, we explore the role of interleukin-1β (IL-1β) in modulating AMD-associated chemokines Ccl2, Cxcl1, and Cxcl10 during photo-oxidative retinal damage, and the effect on both the accumulation of outer-retinal macrophages, and death of photoreceptors.MethodsInhibition of retinal IL-1β expression was performed using either siRNA or antibody neutralisation, which was intravitreally injected in SD rats prior to photo-oxidative damage. Changes in the expression and localisation of Il-1β, Ccl2, Cxcl1 and Cxcl10 genes were assessed using qPCR and in situ hybridisation, while the recruitment of retinal macrophages was detected using immunohistochemistry for IBA1. Levels of photoreceptor cell death were determined using TUNEL.ResultsPhoto-oxidative damage elevated the expression of Il-1β and inflammasome-related genes, and IL-1β protein was detected in microglia infiltrating the outer retina. This was associated with increased expression of Ccl2, Cxcl1, and Cxcl10. Intravitreal IL-1β inhibitors suppressed chemokine expression following damage and reduced macrophage accumulation and photoreceptor death. Moreover, in Müller and RPE cell cultures, and in vivo, Ccl2, Cxcl1 and Cxcl10 were variously upregulated when stimulated with IL-1β, with increased macrophage accumulation detected in vivo.ConclusionsIL-1β is produced by retinal microglia and macrophages and promotes chemokine expression by Müller cells and RPE in retinal degeneration. Targeting IL-1β may prove efficacious in broadly suppressing chemokine-mediated inflammation in retinal dystrophies such as AMD.
Highlights
Chemokine signalling is required for the homing of leukocytes during retinal inflammation, and is associated with pathogenesis of diseases such as age-related macular degeneration (AMD)
We find that inhibiting IL-1β, either via antibody neutralisation or targeted small interfering Ribonucleic acid (RNA), suppresses the expression of Retinal pigment epithelium (RPE)- and Müller cellassociated chemokines Ccl2, Cxcl1, and Cxcl10, reduces accumulation of macrophages in the outer retina, and mitigates photoreceptor death
Expression of retinal IL-1β in relation to chemokine up-regulation and macrophage infiltration following photo-oxidative damage Retinal expression of Il-1β and genes associated with inflammasome assembly and activation (Casp1, Casp8, and Nlrp3) were assessed by quantitative real-time PCR (qPCR) following 24 h photo-oxidative damage (Fig. 1a)
Summary
Chemokine signalling is required for the homing of leukocytes during retinal inflammation, and is associated with pathogenesis of diseases such as age-related macular degeneration (AMD). One of the characteristics of atrophic or ‘dry’ AMD, is the accumulation of microglia/macrophages in the outer retina and subretinal space [2,3,4,5,6]. Homing of leukocytes, such as macrophages, to sites of neuronal damage is orchestrated in part by the co-ordinated expression of chemokines (reviewed in [7]). The Ccl2-Ccr signalling axis has been well-studied in relation to retinal disease, and ablation or pharmacological inhibition of the ligand or receptor exacerbates pathology in laser-induced neovascularisation and photo-oxidative damage models [10,11,12]
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