Signaling through the P2X7 receptor for ATP induces psoriasis-like inflammation in human skin (120.28)

Abstract

Abstract Current therapeutics for psoriasis includes the use of systemic acting immuno-suppressive drugs; however, long-term effects of these treatments remain a concern. A better understanding of the mechanism(s) involved in psoriasis pathogenesis is highly relevant for developing refined therapeutics. However, the immunological processes that perpetuate psoriatic lesions, particularly factors that stimulate DCs to bias autoimmune Th17 responses, are not well known. It is likely that alarmins, such as ATP, play a pivotal role in the pathogenesis by positive-feedback inflammatory mechanisms that break immunological self-tolerance and perpetuate immune responses. We have demonstrated the presence of P2X7R, an ATP receptor, in lesional and non-lesional psoriatic skin, suggesting a principal difference in skin of psoriasis patients and not just a change due to inflammation. Mechanistically, utilizing human cutaneous models, we determined that signaling via P2X7R initiates psoriasis-like inflammation in skin by mechanisms that include innate immunity, DC17 differentiation, and the induction of Th17 biased responses. Furthermore, our results define a prospective role for P2X7R signaling in perpetuating psoriasis lesions by stimulating the mir-21/VEGF pathway. In conclusion, we have begun to describe a potential mechanism of psoriasis lesional formation in humans, which will contribute to understanding the pathogenesis of psoriasis and lead to the development of refined therapeutics.