| dc.description.abstract | Autophagy is an integral process utilised by keratinocytes to undergo terminal differentiation to form the appropriately stratified epidermal layer of skin. Although the inflammatory process in psoriasis is well characterized, little is known about how it affects epidermal autophagy. Autophagy pathway impairment could critically disrupt the homeostatic balance between the differentiation and proliferation status of keratinocytes thus leading to epidermal conditions such as psoriasis characterised by increased inflammation, hyperproliferation and altered differentiation of keratinocytes. This project provides evidence that inflammation exerts its effects by impairing the autophagy pathway and consequently impaired autophagy becomes a hallmark characteristic of psoriasis. This study utilises a well-characterised keratinocyte cell line (NTERT) as well as two recently established SV40-largeT-antigen immortalized keratinocyte models from lesional psoriatic skin (PSA), and a corresponding control from healthy skin (KT2). We found that autophagy flux is intact in both control cell lines but is impaired in the psoriatic PSA cell line. Adding an inflammatory stimulus to cell cultures found that all lines had autophagy disrupted. These results were validated in vivo via fluorescent immunohistochemistry analysis of human skin samples which show that key autophagy proteins are significantly deregulated in lesional psoriatic samples compared to non-lesional psoriatic skin and healthy control skin samples. Analysis of transcriptomic data also found that the expression of key autophagy genes is deregulated in psoriasis patients compared to control populations. Promisingly, we found that treatment of our inflamed cell lines with ethanolamine, a precursor molecule to phosphatidylethanolamine, could restore autophagy in inflamed cells. Treatment with ethanolamine could also activate autophagy flux in PSA cells which previously did not show evidence of intact autophagy flux. These findings suggest that impairment in autophagy driven by inflammation is a crucial driver of psoriasis pathogenesis and pro-autophagic agents could potentially offer a new paradigm of treatment modalities for patients. | en_US |
