Psoriasis is an inflammatory disorder which leads to the improper stratification of epidermal keratinocytes. Autophagic flux analysis of our established cell lines has shown that autophagy is functionally active in healthy keratinocytes but is impaired in psoriatic keratinocytes. To mirror psoriasis in vitro we custom-made a cytokine cocktail that induced IL-1β release in keratinocyte cultures. Stimulation of healthy keratinocytes by this chronic inflammatory cocktail similarly causes autophagy block and accumulation of key autophagy proteins. Interestingly, the inflammatory stimulus causes LC3-I accumulation, rather than LC3-II, suggesting that inflammation blocks autophagy prior to the final stages of autophagosome and autolysosome formation. In addition, p62 upregulation indicates a disruption of cargo degradation via the lysosomal autophagy compartment. Increased ATG4, ATG7 and ATG12 expression indicates that these were not the cause of the block in the pathway. Changes in phospholipid metabolism has been reported in inflammatory skin conditions including Phosphatidylethanolamine (PE) downregulation in psoriatic keratinocytes. In autophagy PE is essential for LC3-I conversion to LC3-II. By inducing PE production in inflamed keratinocytes, we show restoration of the autophagy pathway functionality. Transcriptomic data analysis identified several autophagic genes with significantly deregulated expression in psoriatic samples (n=398) compared to healthy matched or non-matched (n=587) controls. Immunofluorescence staining of healthy and psoriatic human skin samples confirmed differences in key autophagy marker expression and deregulation of lysosomal membrane proteins. We have shown that chronic inflammation in keratinocytes impairs autophagic flux by downregulating PE expression and altering the lysosomal compartment integrity. Our data supports autophagy stimulation as a beneficial approach to counteract chronic inflammatory skin conditions such as psoriasis.

ESDR347 - Chronic Inflammation of Keratinocytes Leads to Autophagy Impairment in Psoriasis

The scientific meeting of the European Society for Dermatological Research (ESDR) is held yearly, usually in September. With an international attendance of more than 1000 skin scientists from around the globe, the four-day event includes short oral presentations from peer-reviewed abstracts, keynote lectures from international experts, sponsored symposia, satellite programs, educational events as well as an important focus on posters, networking and building collaborations amongst scientists. For more information about this year’s meeting visit our website.