Investigating the role of IL-36 cytokines in mediating angiogenesis and vascular permeability
Citation:
Fahey, Erin, Investigating the role of IL-36 cytokines in mediating angiogenesis and vascular permeability, Trinity College Dublin.School of Medicine, 2021Download Item:
Abstract:
Neovascular blinding conditions including age related macular degeneration and diabetic retinopathy are the most common causes of blindness in the elderly and working age populations respectively. Currently the best-in-class therapeutics for these conditions are various VEGF inhibitors. However, due to the failure of some patients to respond to anti-VEGF therapy and the diminishing returns of this treatment with continued use, there is a drive to identify novel therapeutics that can act in parallel with or as an alternative to anti-VEGF. Members of the IL-1 family of cytokines have been shown to be potent regulators of angiogenesis, and many have also demonstrated the ability to regulate vascular permeability. Using human retinal microvascular endothelial cells (HRMEC), we established that IL-36 cytokines could drive angiogenic processes in vitro, including migration, proliferation, and tube formation. We also observed that IL-36 cytokines could reduce vascular permeability significantly, which coincided with increases in expression of endothelial junctional components. Using laser induced CNV as a model of neovascular blinding conditions, we demonstrated that intravitreal administration of IL-36α could significantly reduce the size of the CNV lesion, whereas IL-36β treatment resulted in decreased vascular permeability, observed in both the CNV lesions themselves and in the vasculature of the retina. We had noted that there were certain similarities between the activity of IL-36 cytokines and angiopoietin-1 - a factor that in vitro drives angiogenesis and decreasing permeability and is of therapeutic interest in neovascular AMD due to its ability to decrease both CNV lesion size and permeability. Hyper expression of Ang1 results in increased vessel tortuosity, and analogous to this we showed IL-36RA mice, which have exacerbated IL-36 signalling, display elevated levels of tortuosity and increased vessel density in their retinal vasculature. Finally, we attempted to unearth some of the pathways through which IL-36 alters angiogenesis and vascular permeability. RNA sequencing confirmed that IL-36 treatment in HRMEC enriched pathways associated with angiogenesis and cell adhesion, with genes like claudin-5 being significantly upregulated. It additionally indicated that IL-36 stimulation resulted in the enrichment of anti-viral pathways. We found that IL-36 could activate STAT transcription factors in HRMEC in a JAK dependent manner, yet this activation was not involved in IL-36 mediation of angiogenesis or vascular permeability. Interestingly, IL-36 driven STAT activation was conserved in iBMDM, suggesting a novel conserved role of IL-36 signalling as a direct activator of STAT.
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Trinity College Dublin (TCD)
Science Foundation Ireland (SFI)
Description:
APPROVED
Author: Fahey, Erin
Advisor:
Doyle, SarahPublisher:
Trinity College Dublin. School of Medicine. Discipline of Clinical MedicineType of material:
ThesisCollections
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Full text availableKeywords:
IL-36, Vascular permeability, angiogenesis, IL-1 family cytokinesMetadata
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