Exploring the Role of the Inflammasome Pathway in Diabetic Retinopathy

Background: Diabetic retinopathy (DR) is the leading cause of vision loss among working-age adults worldwide, yet current treatments are inadequate to halt its progression. Studies suggest that dysregulated nucleotide-binding oligomerization domain (NOD)-like receptor protein 3 (NLRP3) inflammasome activation, which orchestrates inflammation in the innate immunity, is associated with DR. However, the impact of inflammasome activation on DR progression remains uncertain. Therefore, this thesis seeks to investigate the role of inflammasome activation in DR progression. Methods: Expressions of inflammasome-associated proteins were characterised in human retina and vitreous of donors without diabetes and donors with diabetes without and with DR. Correlation between markers of activated inflammasome and DR severity as well as the relationship between systemic and ocular inflammasome activation were assessed in a systematic literature review (SLR). To evaluate the use of systemic inflammasome biomarkers in predicting DR progression, plasma inflammasome biomarker levels pre- and post-bariatric surgery were measured in patients who regressed, remained stable, or progressed in DR post-surgery. The role of interleukin (IL)-18, an inflammasome activation biomarker, in DR pathogenesis was further examined using a novel human organotypic retinal culture (HORC) model, where donor retinal explants were cultured in IL-18 without and with high glucose. Results: The NLRP3 inflammasome is activated at the onset of DR, and a significant increase in vitreous IL-18 levels was found in donors with DR compared to normal controls. The SLR demonstrates a correlation between systemic and vitreous levels of IL-1β and IL-18 and DR progression. Plasma analysis of bariatric surgery patients suggests that the group with DR progression exhibited a greater relative increase in IL-18 and C-reactive protein (CRP) levels post-surgery compared to the regressed and stable groups. Using the HORC model, IL-18 in high glucose was able to prime, but not activate, the inflammasome in donor retinal explants. Conclusion: NLRP3 inflammasome activation in the human retina occurs at early stages of DR, and that both increased systemic and intraocular inflammasome activation correlate with increased DR severity. Therefore, inhibiting inflammasome activation presents a therapeutic approach to stop DR progression. Furthermore, systemically elevated levels of CRP, a commonly measured systemic inflammation marker, can potentially be used to predict DR progression, suggesting the potential of a blood-based DR progression screening tool.

Name thesis:degree_name

PhD

Level thesis:degree_level

Doctoral

Discipline thesis:degree_discipline

Ophthalmology

Grantor dc:publisher

ResearchSpace@Auckland

Year dc:date.issued

2024

Author dc:creator

• Kuo, Charisse Yu-Jean

Advisors dc:contributor.advisor

• Mugisho, Lola
• Rupenthal, Ilva
• Murphy, Rinki

Statement dc:rights

• Items in ResearchSpace are protected by copyright, with all rights reserved, unless otherwise indicated.

Licence dc:rights.uri

• https://researchspace.auckland.ac.nz/docs/uoa-docs/rights.htm

Handle dc:identifier.uri

https://hdl.handle.net/2292/70120

OAI identifier oai:identifier

oai:researchspace.auckland.ac.nz:2292/70120