Signaling through the P2X7R for ATP induces human cutaneous innate and adaptive Th17 responses. (P4110)

Abstract

Abstract Human cutaneous 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. We hypothesize that alarmins, such as ATP, 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. Utilizing an ex vivo human cutaneous model, we have determined that signaling purinergic receptors, predominantly P2X7R, via an ATP analog initiates 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 non-lesional and lesional psoriatic skin compared to normal healthy tissues. Interestingly, there was also a P2X7R variant highly expressed in lesional psoriatic skin compared to non-lesional psoriatic and normal healthy skin. 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.