Keratinocyte exosomes activate neutrophils and enhance skin inflammation in psoriasis

Psoriasis is a chronic inflammatory skin disease that severely affects patients physiologically and psychologically. The pathogenesis involving communication between psoriatic keratinocytes and infiltrated immune cells such as neutrophils remains unclear. Exosomes are emerging mediators of intercellular communication. Herein we aim to investigate the release and function of psoriatic keratinocyte exosomes, which have not been illustrated to any extent. We first isolated exosomes from both healthy and psoriasis-like keratinocytes treated with psoriatic cytokine cocktail. These exosomes were observed to be endocytosed by neutrophils. Unlike non cytokine-treated keratinocyte exosomes, cytokine-treated keratinocyte exosomes significantly induced NETosis (the process by which neutrophils produce and release neutrophil extracellular traps) and the expressions of IL-6, IL-8, and TNF-alpha in neutrophils. Proteomic analysis showed that cytokine-treated keratinocyte exosomes exhibited a specific protein profile with proteins enriched in immune-related pathways. We then confirmed that NF-kappa B and p38 MAPK signaling pathways were activated in neutrophils stimulated by cytokine-treated keratinocyte exosomes and were responsible for the expressions of proinflammatory factors mentioned above. Finally, we verified in vivo that cytokine-treated keratinocyte exosomes participated in the skin lesion development of imiquimod-induced psoriasis-like mouse model. Collectively, we reveal that the release of exosomes works as a way of keratinocyte-neutrophil communication, indicating that keratinocyte exosomes, with their specific cargoes, are therapeutic candidates for psoriasis.