Small extracellular vesicles containing miR-381-3p from keratinocytes promotes Th1/Th17 polarization in psoriasis

Abstract T helper cells are crucial for psoriasis pathogenesis. Communication between T cells and psoriatic keratinocytes help drive the Th1/Th17 response, but the underlying mechanism is not well understood. Small extracellular vesicles (sEVs) are emerging mediators of intercellular communication. Here, we investigated the role of keratinocyte-derived sEVs in the Th1/Th17 response in psoriasis. We isolated and characterized sEVs from keratinocytes under normal (untreated) and psoriatic (cytokine-treated) conditions. SEVs under both conditions exhibited a cup-shaped morphology and expressed markers CD63 and CD81. SEVs from cytokine-treated keratinocytes can be taken up by CD4+T cells, leading to induction of Th1/Th17 polarization. Small RNA sequencing revealed that miR-381-3p was significantly increased in sEVs from cytokine-treated keratinocytes and in CD4+T cells from psoriatic patients. Moreover, sEVs containing miR-381-3p was responsible for sEVs-induced Th1/Th17 polarization. We further found that miR-381-3p targeted to the 3' UTR of E3 ubiquitin-ligase UBR5 and stabilized RORγt protein expression. It also targeted to the 3' UTR of Foxo1, associated with activated T-bet and RORγt transcription. Taken together, we propose that psoriatic keratinocytes transfer miR-381-3p to CD4+T cells via sEVs, inducing Th1/Th17 polarization and promoting psoriasis development. Our findings motivate future studies of keratinocyte-derived sEVs, or their specific cargoes, as therapeutic candidates for psoriasis.