Human cutaneous dendritic cells (DCs) have the ability to prime and bias Th17 lymphocytes. However, the factors that stimulate cutaneous DCs to induce Th17 responses are not well known. Alarmins, such as ATP, likely play a pivotal role in the induction and maintenance of cutaneous immune responses by stimulating DC maturation, chemotaxis, and secretion of IL-1β and IL-6, Th17-biasing cytokines. In this study, using a well-established human skin model, we have demonstrated that signaling purinergic receptors, predominantly the P2X7 receptor (P2X7R), via an ATP analog initiate innate proinflammatory inflammation, DC17 differentiation, and the subsequent induction of Th17-biased immunity. Moreover, our results suggest a potential role for P2X7R signaling in the initiation of psoriasis pathogenesis, a Th17-dependent autoimmune disease. In support of this, we observed the increased presence of P2X7R in nonlesional and lesional psoriatic skin compared with normal healthy tissues. Interestingly, there was also a P2X7R variant that was highly expressed in lesional psoriatic skin compared with nonlesional psoriatic and normal healthy skin. Furthermore, we demonstrated that psoriatic responses could be initiated via P2X7R signaling in nonlesional skin following treatment with a P2X7R agonist. Mechanistic studies revealed a P2X7R-dependent mir-21 angiogenesis pathway that leads to the expression of vascular endothelial growth factor and IL-6 and that may be involved in the development of psoriatic lesions. In conclusion, we have established that purinergic signaling in the skin induces innate inflammation, leading to the differentiation of human Th17 responses, which have implications in the pathogenesis and potential treatment of psoriasis.