The respective contributions of P2X7 receptor variants to the development of psoriasiform dermatitis

Abstract

Abstract Psoriasis is a chronic inflammatory cutaneous disease caused by environmental triggers in genetically predisposed individuals which account for 2–3% of the world population. However, the mechanisms contributing to the initialization of psoriasis are largely unknown. ATP is a particularly interesting candidate that, via P2X7 receptor (P2X7R) signaling, can activate NF-κB and the IL-23/IL-17 axis, both of which have been shown to be critical in psoriasis pathogenesis. Moreover, P2X7R expression is increased in lesional and non-lesional skin of psoriatic patients compared to healthy donors. Specifically, we have determined that the canonical P2X7R variant A (P2X7RA) is expressed comparably in both lesional psoriatic tissues and normal human skin. However, it is the alternatively spliced P2X7R variant B (P2X7RB) that is highly expressed in human psoriatic lesions. P2X7RB is widely distributed in human tissues and P2X7RB activation enhances cellular proliferation, decreases ATP-induced apoptosis, and in heterotrimers potentiates the inflammatory responses induced by P2X7RA. Importantly, our studies have established that signaling through the P2X7R induces an acute psoriasiform dermatitis in mice. Thus, our ongoing work is focusing on the specific role of P2X7R variants in inflammatory diseases. We confirmed in human blood derived DCs that signaling through the P2X7RB can induce proinflammatory cytokines, such as IL-1β, IL-6 and TNF-α, to same degree as P2X7RA. In conclusion, this work provides a basic mechanistic insight into local inflammation induced following purinergic signaling through the P2X7R that is likely involved in the pathogenesis and potential treatment of many cutaneous inflammatory diseases.