Regulation of the Microglial Neuroimmune Response by Long Non-Coding RNAs

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PROJECT SUMMARY/ABSTRACT Systemic inflammation due to viral or bacterial infection is a direct cause of dysregulated neuroimmune responses and is linked to several neurodegenerative pathologies such as multiple sclerosis (MS). Microglia participate in innate immune processes of pathogen clearance contributing to both neurorecovery and neurotoxicity. Proper microglial immune function supports neurogenesis and synapse development, regulates homeostatic neuronal and glial activity, and provides host defense against pathogens and injury. Dysregulation microglial immune function is likely to contribute to neuroinflammatory processes that cause neurotoxicity. The mechanisms governing microglial functional plasticity and whether microglial immune responses are neuroprotective or neurotoxic are not well understood. Long intergenic non-coding RNAs (lincRNAs) are prime candidates for regulating microglial plasticity because many lincRNAs are early-primary response genes whose expression is stimulated by environmental signals. LincRNAs are associated with human inflammatory disease and neuropathologies such as MS. Our collaborative work has identified lincRNAs that regulate pro-inflammatory gene expression in TLR4-stimulated macrophages and microglia through modulation of chromatin remodeling. Based on these studies, we hypothesize that differential expression of lincRNAs act as regulators of gene transcription to control microglial expression of neuroprotective or neurotoxic phenotypes. Further, we propose that differential expression of lincRNAs will contribute to whether microglial responses are effective in clearing pathogens and promoting normal function or causing neurotoxicity and promoting neurodegeneration. To address this hypothesis, we mined whole-transcriptome data and used an in vitro model system to identify lincRNAs that are inversely expressed in microglial pro- inflammatory neurotoxic (TLR4-stimulated) and anti-inflammatory neurotrophic (IL-4-stimulated) functional states. Our recently published work shows that lincRNAs are differentially expressed in microglial neuroinflammatory and neurotrophic states and that silencing neuroinflammatory lincRNAs can reduce neurotoxicity. Preliminary evidence shows that specific lincRNAs are overexpressed in degenerating cortical tissue of a mouse model for progressive, chronic MS. The objectives of this proposal are to investigate the mechanisms by which lincRNAs mediate a proinflammatory state in microglia (Aim 1) and to determine whether differential lincRNA expression underlies viral-induced acute and chronic mouse models of MS (Aim 2). This proposal is conceptually innovative as it will provide information about lincRNA-regulated mechanisms of neuroimmunity and neurotoxicity. These studies are directly applicable to the development of new therapeutic strategies for limiting the neurodegeneration associated with inflammatory neuropathologies.