THE ROLE OF THE GLYCOCALYX DURING PSORIASIS-LIKE SKIN INFLAMMATION

Abstract

The glycocalyx is a proteoglycan-rich layer present on the surface of all mammalian cells and is hypothesised to mediate leukocyte migration by acting as a barrier against their adhesion to the endothelium. Little is known about the role of the glycocalyx in skin inflammation, so to investigate this, Aldara cream was used to stimulate psoriasis-like inflammation in mice. In response, elevated levels of the glycocalyx component heparan sulfate (HS) were measured in the blood by ELISA, indicative of glycocalyx shedding. However, flow cytometry and immune-staining revealed no changes in endothelial HS in Aldara-treated skin, thus other sources of HS were examined. HS expression on leukocytes significantly decreased upon the stimulation of skin inflammation, suggesting this may be a source of increased circulating HS. When this degradation of HS on leukocytes was recreated in vitro by treating monocytes with heparinase, the cells were more able to migrate through a transwell. HS is a side chain of the glycocalyx with many functional roles and is cleaved by the heparanase enzyme. Mice were treated with a heparanase enzyme inhibitor, alongside topical application of Aldara cream, to determine whether a protected glycocalyx could affect immune cell migration during skin inflammation. Inhibition of heparanase during psoriasis-like skin inflammation led to reduced numbers of leukocytes in skin, yet unexpectedly, also led to increased clinical signs of inflammation. Tregs are anti-inflammatory cells which are significantly reduced in inflamed skin in response to heparanase inhibition. Depletion of Tregs using anti-CD25 during psoriasis-like skin inflammation also increased clinical signs of inflammation, identifying a lack of these cells as a potential mediator of the exacerbated inflammation seen in Aldara-treated skin with heparanase inhibition. These findings demonstrate the importance of the glycocalyx to immune cell recruitment in inflammation. However, they challenge the current model that these proteoglycans are primarily endothelial and urge caution when considering using heparanase inhibitors as therapies for inflammatory diseases, as anti-inflammatory cell recruitment may also be affected.

Date of Award	6 Jan 2025
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Douglas Dyer (Supervisor), Rachel Lennon (Supervisor), Tracy Hussell (Supervisor) & Amy Saunders (Supervisor)