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Activation of cutaneous innate defense by glycosaminoglycans


Glycosaminoglycans are ubiquitously expressed on cell surfaces and are an essential component of the extracellular matrix. These linear carbohydrate chains may be linked to a protein backbone or associated with other matrix molecules. Following injury or trauma, the extracellular matrix of the skin is broken down, resulting in the release of soluble glycosaminoglycan-derived oligosaccharides from the epidermis and dermis. The release of glycosaminoglycans from their nascent insoluble form at the cell surface and in the extracellular matrix, and processing to alternate sizes, serves as a mechanism to modify their many functions. Following injury, a wound is bathed in a fluid that becomes rich in soluble glycosaminoglycans, of which the dermal glycosaminoglycan dermatan sulfate is a major component. Chapter I investigates the characteristics of dermatan sulfate necessary to facilitate FGF-2 and FGF-7 activity. Active oligosaccharides consisted of decasaccharides and were rich in iduronic acid residues and 4-O-sulfation. Increasing sulfation by forming disulfated disaccharides did not increase the activity of dermatan sulfate. Another glycosaminoglycan, hyaluronan, is normally a large polymer but is present in wounds as small oligosaccharides. In Chapter II, these small hyaluronan fragments were shown to be signals of inflammation, resulting in a 56-fold increase in IL-8. Surprisingly, this effect of hyaluronan was dependent on TLR4. Chapter III further investigates the interaction of hyaluronan with TLR4. Sterile inflammation of the skin was linked to hyaluronan release and was dependent on TLR4. Analysis into the signaling mechanism reveals that hyaluronan requires the co- accessory molecule MD-2, but not CD14. Instead, hyaluronan utilizes CD44 as a co-accessory molecule, as CD44 co- localizes and immunoprecipitates with TLR4. Interestingly, intraperitoneal injection of hyaluronan into mice before lipopolysaccharide injection results in less severe sepsis, suggesting that injury and release of hyaluronan primes the host to alter it's response to ensuing infection. Taken together, this work demonstrates how soluble glycosaminoglycans released following injury regulate events critical to wound healing. A novel pathway connecting specific glycosaminoglycans to growth factor function and microbial pattern recognition is suggested as a mechanism for control of wound repair and inflammation

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