Rôle des cellules myéloïdes dans des modèles murins de la neuroinflammation

Authors: Bozoyan, Lusine
Advisor: Vallières, Luc
Abstract: Inflammation of the central nervous system (CNS), known as neuroinflammation, is a hallmark of chronic neurodegenerative diseases such as multiple sclerosis (MS) and Alzheimer’s disease (AD). Detailed characterization of each cell population and its specific molecular signature in different pathologies will allow us to master and, thus, control neuroinflammatory processes. The present work aimed to understand the mechanisms of action of two types of myeloid cells, microglia and neutrophils, in various models of CNS disorders. The specific goals of my research were: (a) understanding the role of IL-36 in neuroinflammation established during experimental autoimmune encephalomyelitis (EAE); (b) evaluating the implication of GPR84, a G-protein coupled receptor, which is specifically expressed by microglia in the CNS during cognitive function alterations in a transgenic mouse model of AD. Our results showed that the levels of IL-36/IL-36R signalling pathway elements are increasing in three different models of EAE, however they contribute neither to the development nor to the progression of this pathology. Using flow cytometry we identified neutrophils as a major source of IL-36γ. Moreover, we demonstrated that microglia express IL-36R and their stimulation with IL-36γ results in the production of pro-inflammatory cytokines. In the second part of our research, we characterized the increase of GPR84 expression on microglia during AD progression using APP/PS1 mice. Crossing these mice with GPR84 deficient mice decreases the activation and the recruitment of microglia around β-amyloid plaques and accelerates the cognitive decline. Our data imply an important role for GPR84 in the maintenance of neuronal homeostasis since its lack contributes to the dendritic degeneration in the brain. Discoveries made during my studies provide new and valuable insights that may contribute to the development of efficient therapies targeting myeloid cells in different CNS pathologies. My results open up new avenues to elucidate the role of IL-36γ in neurodegenerative diseases. Furthermore, through my work, we introduce an in vivo model for identifying the endogenous ligand of GPR84, which is a potential therapeutic target for prevention and/or treatment of AD.
Document Type: Thèse de doctorat
Issue Date: 2016
Open Access Date: 24 April 2018
Permalink: http://hdl.handle.net/20.500.11794/27007
Grantor: Université Laval
Collection:Thèses et mémoires

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