The goals of the proposed study are to determine the mechanisms by which TNF, an important component of neuroinflammation, upregulates IL15 production in the endothelial cells of the blood-brain barrier (BBB), the transport of IL15 across the BBB, and the resulting pathophysiological implications for neuroinflammatory and autoimmune disorders. The proinflammatory cytokine TNF not only crosses the BBB to exert its multipotent effects, but it also modulates the endothelial signaling and permeation of other cytokines. IL15 and its receptors show specific and robust upregulation in cerebral microvessel endothelial cells challenged by TNF or lipopolysaccharide, shown by microarray, qPCR and immunohistochemistry in our preliminary results. We will address the overall hypothesis that IL15 potentiates the effects of TNF in the CNS with four aims. (1) Test the hypothesis that TNF upregulates IL15 transport. We will identify the roles of IL15 receptors in transporting IL15 by use of in-situ brain perfusion studies in receptor knockout and wildtype mice, determine the effects of TNF on the transcellular permeability of IL15 in primary cerebral microvessel endothelial cells cultured in the Transwell system, and determine the differential roles and interactions of IL15R1, IL2R2, and IL2R3 receptors in TNF-facilitated IL15 transcytosis by immunofluorescent trafficking studies. (2) Test the hypothesis that TNF stimulates protein synthesis and basolateral secretion of IL15 from the endothelial cells of the BBB. This will be achieved by protein translation and turnover assays, confocal analyses of time-dependent colocalization of IL15, its receptors, and intracellular organelles, and quantification by enzyme-linked immunosorbent assay. We will also test the mediating effect of prostaglandins in the TNF-induced increase of the basolateral secretion of IL15. (3) Test the hypothesis that an upregulated endothelial IL15 system enhances TNF-induced neuroinflammation, shown by fever, sickness behavior, reactive gliosis, and cerebral production of proinflammatory cytokines. Apart from studies on mice to test the effects of soluble IL15 receptors in blocking these effects, the inflammatory changes in cultured cerebral microvessel endothelial cells obtained from knockout and wildtype mice will also be identified. (4) Test the hypothesis that an upregulated IL15 system exacerbates experimental autoimmune encephalomyelitis (EAE), a disorder of neuroimmune modulation and a model for multiple sclerosis. The regulatory changes of IL15 permeation across the BBB of the EAE mice will be determined, and the effects of soluble receptors in reducing the symptoms and disease burden of EAE will be determined. The feasibility of the studies is supported by preliminary results, our past experience, and the literature. By completion of the proposed studies, we will acquire novel and essential understanding of IL15 and IL15 receptor trafficking in cerebral endothelial cells, and identify new therapeutic targets for intervention in neuroinflammation and CNS autoimmune diseases.
Neuroinflammation is a common etiology in many CNS disorders, including infection (bacterial, fungal, viral, and parasitic), neuroAIDS, stroke, global hypoxia, autoimmune diseases (e.g., multiple sclerosis, transverse myelitis, acute disseminating encephalomyelopathy), tumor, a variety of neurodegenerative disorders (e.g., Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis), and even diabetes and the metabolic syndrome. Multiple sclerosis (MS) is a devastating and progressive disorder with an age of onset typically between 20 and 40. There are about 250,000 - 350,000 people in the United States with MS diagnosed by a physician. This estimate suggests that about 200 new cases are diagnosed each week. The proinflammatory cytokines TNF and IL15 play important roles in the initiation, progression, and resolution of neuroinflammation and autoimmune disorders of the CNS. Their interactions with the blood-brain barrier largely determine the final outcome of these blood-borne cytokines.
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