The doctoral dissertation in the field of Immuno-Ophthalmology will be examined at the Faculty of Health Sciences at Kuopio campus. The public examination will be streamed online (in Finnish).
What is the topic of your doctoral research? Why is it important to study the topic?
In this doctoral dissertation on the field of Biomedical sciences (Immuno-Ophthalmology), the mechanisms of inflammation underlying age-related macular degeneration and UV radiation-induced corneal inflammation were studied at the cellular level. More specifically, inflammasome activation and the subsequent cytokine response were examined in human corneal epithelial and retinal pigment epithelial cells. Inflammasomes are tightly regulated intracellular protein complexes capable of sensing cytosolic perturbance that can be detrimental for cellular homeostasis. Danger signal recognition by an inflammasome receptor leads to the formation of inflammasome protein complex, which results in the enzymatic activation of caspase-1 and the subsequent maturation of interleukin-1beta (IL-1b) and IL-18 into their active forms.
Normally, inflammasome activation is an important element in human immune defense and it is initially a beneficial response to cellular stress e.g., in microbial infections or tissue damage. Recently, dysregulated and non-infectious inflammasome activation has been associated with many chronic inflammatory diseases, such as age-related macular degeneration, that is the most common eye disease among the elderly in the Western world causing significant impairment in vision. The majority of patients suffer from the disease form that lacks any medical treatment at the moment. Therefore, it is crucial to study the pathogenesis of age-related macular degeneration in order to identify potential targets to stop and possibly prevent the disease progression.
What are the key findings or observations of your doctoral research?
Previous studies have shown that excessive or prolonged exposure to UV can induce inflammation in the cornea. In this dissertation, it was found that ultraviolet B (UVB) irradiation is able to activate also NLRP3 inflammasome in human corneal epithelial cells. Moreover, inflammasome activation in human corneal epithelial cells was diminished by a potential drug molecule, cis-urocanic acid (cis-UCA), which is a naturally occurring chromophore in human epidermis. In addition, inflammasome activation was prevented by cis-UCA in human retinal pigment epithelial cells suffering from UVB-induced photochemical damage. In line with that, cis-UCA protected human retinal pigment epithelial cells from the UVB-induced DNA damage and cell death.
Age-related macular degeneration is a multifactorial retinal disease. Declined intracellular protein clearance and excessive ROS production have been demonstrated to contribute to age-related macular degeneration causing also an elevated inflammasome activation in human retinal pigment epithelial cells. However, less attention has been paid to whether mitochondrial dysfunction induces inflammasome activation in human retinal pigment epithelial cells. In this dissertation, it was found that mitochondrial damage is able to activate two separate inflammasome complexes (NLRP3 and AIM2) in these cells. Typically, one inflammasome complex can regulate the production of IL-1b and IL-18 via the same signaling pathway but in this thesis, it was found that simultaneously produced IL-1b and IL-18 can be regulated by separate signaling routes in human corneal epithelial and retinal pigment epithelial cells.
How can the results of your doctoral research be utilised in practice?
The results of this dissertation improve the understanding of molecular mechanisms underlying inflammasome activation in age-related macular degeneration and UV radiation-induced corneal inflammation. In particular, AIM2 inflammasome is a novel topic in the field of eye research. Since dysregulated inflammasome activation has been linked to many inflammatory long-term diseases in addition to age-related macular degeneration, the results of this dissertation can be utilized more broadly in the field of biomedical sciences.
What are the key research methods and materials used in your doctoral research?
Cell experiments were performed using several cultures of human corneal epithelial and retinal pigment epithelial cells. Cell responses were measured after a variety of cell exposures (e.g., to inhibitors, activators, or transfections) using cell and molecular biology research methods, such as ELISA, western blot, quantitative RT-PCR, cytotoxicity measurements, immunocytochemistry, confocal microscopy, and enzyme activity measurements. The dissertation consists of five publications and their experimental part has been performed in Professor Anu Kauppinen’s Immuno-Ophthalmology research group in collaboration with the Kaarniranta AMD Lab research group.
The doctoral dissertation of Eveliina Korhonen, MSc, entitled Inflammasome activation in response to aberrations of cellular homeostasis in epithelial cells from human cornea and retina will be examined at the Faculty of Health Sciences. The Opponent in the public examination will be Professor Kari Eklund of the University of Helsinki, and the Custos will be Professor Anu Kauppinen of the University of Eastern Finland.
For further information, please contact:
Eveliina Korhonen, MSc, eveliina.korhonen(a)uef.fi
