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Role of RIP3 in Neuroinflammation in the Postnatal Mouse Brain
Inflammation in the developing central nervous system (CNS) can contribute to numerous issues in the fully developed adult. Uncovering pathways responsible for the inflammation is valuable for future intervention strategies aimed at preventing or reducing inflammation. Receptor interacting protein kinase 3 (RIP3) has recently been identified as a critical signaling molecule in initiating programmed necrosis (also termed necroptosis), which may contribute to cell damage and subsequent inflammation under pathophysiological conditions such as stroke and traumatic injury. The goal of this study was to use genetic approaches to determine the role of RIP3 in brain immune responses after systemic inflammatory challenge and the contribution of RIP3 to inflammation-induced potentiation of hippocampal injury in an ex vivo model of hypoxia/ischemia. Stimulation with lipopolysaccharide (LPS) elicited robust proinflammatory responses of organotypic hippocampal slices and significantly exacerbated CA1 neuronal excitotoxicity after subsequent oxygen glucose deprivation (OGD). Genetic ablation of RIP3 resulted in decreased levels of interleukin-1[lowercase beta symbol] (IL-1[lowercase beta symbol]) after LPS stimulation and suppressed excitotoxicity after subsequent OGD challenge. These results suggest that activation of RIP3 increases proinflammatory responses in cultured hippocampal slices. To determine if RIP3 regulates inflammation in vivo, we examined cytokine and chemokine levels of the brain after subcutaneous LPS administration followed by hypoxia in early postnatal pups. Mice lacking RIP3 produced significantly lower levels of proinflammatory cytokine IL-1[lowercase beta symbol] 6-24 hours after LPS administration when compared to wildtype RIP3^+/+ littermates. In contrast, 4 and 21 days after LPS administration followed by hypoxia, IL-1[lowercase beta symbol] and other proinflammatory cytokine transcript levels in the brain were drastically diminished and were comparable between RIP36^+/+ and RIP3^-/- mice. Our preliminary data suggest that these RIP3^-/- mice show lower expression of genes responsible for myelination. In summary, our results demonstrate, for the first time, that RIP3 mediates proinflammatory responses in the CNS by enhancing IL-1[lowercase beta symbol] production and imply that RIP3 is a potential target for neuroinflammatory disorders. The electronic version of this dissertation is accessible from http://hdl.handle.net/1969.1/155480
Master of Science Texas A & M University 2015 http://hdl.handle.net/1969.1/155480