The impact of systemic immune system activation on the retina: implications for age-related macular degeneration

Abstract

Age-related macular degeneration (AMD) is a neurodegenerative disease of the retina and the leading cause of blindness in the UK. Genetic studies and mouse models demonstrate a clear role for local immune activation in AMD pathology, but it is not clear whether systemic inflammation can contribute to AMD pathology. Systemic inflammation, particularly due to bacterial infection, has been shown to exacerbate neurodegeneration in Alzheimer’s and Prion disease. There is also evidence that patients who have been exposed to chronic bacterial infections (i.e. periodontitis, pneumonia) are at increased risk of AMD development. Consequently, this thesis tests the hypothesis that systemic inflammation can contribute to the progression of AMD by exacerbating local inflammation in the retina, leading to earlier development of blindness.

Systemic bacterial (Salmonella) infection induced retinal microglial activation, Müller cell activation, T cell recruitment and pro-inflammatory cytokine production in mice. When subsequent peripheral immune stimulation was induced by LPS, retinal inflammation was reduced, indicating a protective mechanism. However, during ongoing local retinal inflammation induced by immune complexes, systemic inflammation exacerbated the recruitment of immune cells to the subretinal space. No retinal degeneration was observed in this model, so a novel laser-induced model of acute outer retinal atrophy was developed showing RPE dysfunction, photoreceptor loss, functional deficits and inflammation mimicking aspects of human geographic atrophy. This model could be used to investigate the interaction of systemic inflammation and degeneration, gaining insights into AMD pathobiology. In AMD patients, increased aqueous humour IL-8 was identified compared to age-matched controls but no differences in serum cytokine levels were observed at baseline or in whole blood cultured with various immune stimuli.

Data from mouse experiments indicate that systemic infections can induce chronic retinal inflammation and, during local inflammation, immune cell recruitment to the subretinal space - the site of AMD pathology. Meanwhile, human data demonstrates that local inflammation in AMD patients does not arise due to an exaggerated systemic inflammatory response to infections.

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Identifiers

ORCID for Jessica Teeling: orcid.org/0000-0003-4004-7391

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