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

Abstract

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.