Chondroitin sulfate proteoglycans as novel mediators of inflammation in multiple sclerosis
Date
2018-07-23
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Abstract
The extracellular matrix of the central nervous system is an interconnected network of proteins and sugars. The extracellular matrix is crucial for homeostasis, but its remodeling in diseases impacts both injury and repair. Here I introduce an extracellular matrix member that participates in immune-matrix interactions, the chondroitin sulfate proteoglycans. Chondroitin sulfate proteoglycans integrate signals from the microenvironment to activate immune cells, interact with their receptors, and bind signaling molecules such as cytokines and chemokines. Chondroitin sulfate proteoglycans are commonly upregulated in a variety of neuroimmune and peripheral inflammatory diseases, and are key drivers of pathogenesis. In this thesis, I characterized the upregulation of chondroitin sulfate proteoglycans in the inflammatory demyelinating mouse model of multiple sclerosis, experimental autoimmune encephalomyelitis. One novel observation was the upregulation of chondroitin sulfate glycosaminoglycans and the chondroitin sulfate proteoglycan member versican V1 at peak inflammation, as well as their accumulation in the perivascular cuff, a portal of entry of immune cells into the central nervous system. Chondroitin sulfate proteoglycans augmented the inflammatory activity of macrophages, enhancing the production of pro-inflammatory cytokines, matrix-degrading enzymes, and promoting their migration and phagocytosis. I explored the various mechanisms underlying this pro-inflammatory response. I found that receptors involved in the response to chondroitin sulfate proteoglycans may include toll-like receptor -2 and -4, and downstream signaling molecules include the adaptors MyD88 and TRIF as well as NFkB and protein kinase C. Lastly, I screened novel fluorinated glucosamine and xyloside compounds for their ability to interfere with chondroitin sulfate proteoglycan production and in other assays pertinent to multiple sclerosis. I found the compound, Ac-4,4-diF-GlcNAc, was extremely potent at reducing CSPG synthesis by astrocytes, promoting oligodendrocyte precursor cell growth on an inhibitory matrix, and had non-toxic but anti-inflammatory capabilities. Following experimental autoimmune encephalomyelitis, Ac-4,4-diF-GlcNAc treatment significantly reduced clinical disease score in multiple treatment paradigms, and reduced the number of infiltrating leukocytes in the spinal cord. This thesis highlights novel roles of chondroitin sulfate proteoglycans in inflammation, details mechanisms for their effects on immune cells, and also highlights a novel compound that may be beneficial for targeting chondroitin sulfate proteoglycans to control inflammatory cascades.
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Keywords
Multiple Sclerosis, central nervous system, Chondroitin sulfate proteoglycans, extracellular matrix
Citation
Stephenson, E. L. (2018). Chondroitin sulfate proteoglycans as novel mediators of inflammation in multiple sclerosis (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca. doi:10.11575/PRISM/32696