Harnessing the Immunomodulation of UV-Exposed Keratinocyte Extracellular Vesicles for Inflammatory Disorder Treatment

Abstract

<p>Sunbathing excessively heightens the risk of skin carcinogenesis due to ultraviolet (UV)-mediated immunosuppression. Keratinocytes, the primary cells in epidermis, play a pivotal role in orchestrating the UV-induced immunosuppressive response by releasing platelet-activating factor (PAF) upon UV exposure. Adopting a paradigm shift that transforms a known health hazard as a potential therapeutic asset, a novel therapeutic strategy is set out to investigate for inflammatory conditions by leveraging immunosuppressive properties of UV-irradiated keratinocytes. To safely exploit this mechanism, extracellular vesicles are isolated from UV-irradiated keratinocytes, designate ^UVKEV, and assess their potential as immunomodulatory agents in the mouse model of inflammatory bowel disease (IBD) and imiquimod (IMQ)-induced psoriasis. Subcutaneous administration of ^UVKEV efficiently stimulates the secretion of prostaglandin E2 (PGE2) by keratinocytes and promotes the migration of mast cells to lymph nodes through the PAF/PAF receptor pathway. The as-prepared ^UVKEV effectively reshapes the immune landscape within the spleen by inhibiting dendritic cell maturation and increasing the population of regulatory T cells. Animal studies confirm that ^UVKEV can result in robust systemic immune tolerance and significantly alleviate the symptoms of both IBD and psoriasis. This study presents the possibility of ^UVKEV as natural immunoregulatory therapeutics for the managing inflammatory disorders with promising clinical potential.</p>