The Neuroprotective Role Of Vitamin D On Neurons In A Central Nervous System Autoimmune Disease
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Publisher:The Ohio State University
Series/Report no.:The Ohio State University. Biological Sciences Honors Theses; 2015
Multiple sclerosis (MS) is an autoimmune inflammatory disease of the central nervous system (CNS). Childhood vitamin D insufficiency is a known risk factor of MS. However, it remains unclear how vitamin D levels before adolescence affect the susceptibility to disease. We hypothesize that vitamin D increases IL-34 production, which directs microglia into an anti-inflammatory phenotype, preventing neurodegeneration in a developing CNS. We observed an increased expression of IL-34 mRNA in primary neurons and neurons derived from a mouse Neuroblastoma (N2a) cell line after treating with calcitriol, the biologically active form of vitamin D. Additionally, immortalized murine microglia (BV-2) and primary microglia treated with IL-34 showed a decrease in pro-inflammatory cytokines and an increase in anti-inflammatory molecules compared to untreated controls upon lipopolysaccharide (LPS) stimulation. These findings indicate that microglia can be directed to an anti-inflammatory phenotype by IL-34, which is produced by vitamin D-treated neurons. To study how vitamin D signaling in childhood influences the risk of developing disease in vivo, we generated a transgenic mouse model using single-neuron labeling with inducible Cre-mediated knockout (SLICK) mice. This allows manipulation of VDR levels on neurons during different ages of life. We found that SLICK f/+ mice have decreased VDR expression when evaluated by immunohistochemistry. These mice showed that low levels of vitamin D during development caused increased disease severity through inducing experimental autoimmune encephalomyelitis (EAE). By understanding the mechanism by which vitamin D levels influence multiple sclerosis susceptibility, vitamin supplements could be administered to prevent high risk populations from developing this incurable disease.
Academic Major: Biomedical Science