The role of the interleukin-1 family in the development of diabetic retinopathy
"Diabetic retinopathy is one of the most prominent complications of diabetes with approximately 67% of diabetic patients experiencing some form of retinopathy (1). Currently there is no cure for the disease, and in order to develop more reliable therapies a better understanding of mechanisms leading to disease onset and progression are crucial. The aim of this dissertation was to identify underlying mechanisms promoting diabetic retinopathy. Since there is a growing consent that chronic retinal inflammation might be causing and driving the progression of diabetic retinopathy the research was specifically focused on identifying potential mediators and cell types participating in the inflammation, and testing whether targeting specific inflammatory pathways will be a valid therapeutic strategy to treat diabetic retinopathy. First, in order to understand the role of inflammation in diabetic retinopathy we examined the caspase-1/IL-1beta pathway. We demonstrated that caspase-1 activity is increased in the retinas of streptozotocin (STZ)-induced diabetic mice at 10 and 20 weeks of diabetes. Interestingly, elevated caspase-1 activity was prevented in diabetic IL-1R1-/- mice at 20 weeks indicating that sustained caspase-1 activity is dependent on feedback through IL-1R1. The same phenomena was observed in Müller cells in vitro. Furthermore, we identified Receptor Interacting Protein-2 (RIP2) as a central regulator of caspase-1 activity induced by either high glucose or IL-1beta. It was further identified that this caspase-1 activity leads to Müller cell death both in vitro and in vivo. To confirm that the activation of the caspase-1/IL-1beta pathway is indeed responsible for retinal pathologies associated with retinopathy we used the galactosemic mouse model, another model of retinopathy leading to the same vascular pathologies seen in the STZ diabetic mouse model. Knockout of caspase-1 prevented the formation of acellular capillaries in galactosemic mice. When Müller cells were treated with elevated galactose levels, caspase-1 was activated and led to cell death. Interestingly, mediators associated with caspase-1 activation such as Thioredoxin Interacting Protein (TXNIP) and oxidative stress were not induced by galactosemia as they are in hyperglycemic conditions. Finally, to identify potential roles of other IL-1 family members we began to examine the role of IL-1alpha in the activation of the caspase-1/IL-1beta pathway. Our data suggest that IL-1alpha contributes to caspase-1 activity and Müller cell activation since treatment with an IL-1alpha neutralizing antibody inhibited high glucose induced caspase-1 activity. Furthermore, we observed that IL-1alpha appeared to translocate in to the nucleus under high glucose conditions in Müller cells in vitro. Collectively, these findings indicate that caspase-1 activation and subsequent IL-1beta production are crucial for the development and progression of diabetic retinopathy. Müller cells are a prominent site of active caspase-1 in the diabetic retina. It seems that targeting the caspase-1/IL-1beta pathway might be a potential new strategy to develop therapies to treat diabetic retinopathy."--Pages ii-iii.
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- In Collections
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Electronic Theses & Dissertations
- Copyright Status
- In Copyright
- Material Type
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Theses
- Authors
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Feenstra, Derrick J.
- Thesis Advisors
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Mohr, Susanne
- Committee Members
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Parameswaran, Nara
Olson, Lawrence
Gulbransen, Brian
Glazer, Lou
- Date
- 2017
- Subjects
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Interleukin-1
Diabetic retinopathy
- Program of Study
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Physiology - Doctor of Philosophy
- Degree Level
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Doctoral
- Language
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English
- Pages
- xiii, 148 pages
- ISBN
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9781369699609
1369699603