Emerging evidence demonstrates a critical role for inflammasome activation in vitiligo pathogenesis. However, the specific molecular mechanism of inflammasome-dependent melanocyte degeneration in vitiligo is still not clear. Extracellular adenosine triphosphate (ATP) is a versatile mediator of inflammatory processes, which may be involved in vitiligo pathogenesis. This study presents how extracellular ATP, released from keratinocytes by oxidative stress, affects melanocyte survival in vitiligo skins. H2O2-induced oxidative injury increased ATP release from keratinocytes and skin tissues. High concentration of extracellular ATP induced both ROS production and cell death in melanocytes. Treatment with ATP in melanocytes led to caspase-1 activation as well as production of active forms of IL-1β and IL-18 via P2X7 receptor (P2X7R). Lesional and perilesional skins of vitiligo showed higher levels of ATP as well as upregulation of active caspase-1 compared to non-lesional skins, suggesting its possible role in inflammasome activation in vitiligo. Moreover, the expression of CXCL9 in keratinocytes, mediated through ATP-P2X7R-dependent inflammasome activation, was responsible for CLA+ CD8+ T-cell chemotaxis into the skin. In conclusion, extracellular ATP as a danger signal not only activates inflammasome pathway as well as increases cutaneous chemotaxis of CD8+ T cells via CXCL9 in vitiligo.

Adenosine triphosphate-P2X7 axis mediates melanocyte death and skin trafficking of CD8+ T cells by CXCL9 through inflammasome activation in vitiligo