Extracellular adenosine 5ʹ-triphosphate (ATP) is a well-known inflammasome-activating signal. 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. This study presents how extracellular ATP, released from keratinocytes by oxidative stress, affects melanocyte survival in vitiligo skin. H2O2-induced oxidative injury increased ATP release from keratinocytes and skin tissues. The high concentration of extracellular ATP induced both ROS production and cell death in melanocytes. Treatment with ATP caused the activation of caspase-1 as well as the production of active forms of IL-1β and IL-18 via P2X7 receptor in keratinocytes and melanocytes. Lesional and perilesional skin of vitiligo showed higher levels of ATP as well as upregulation of active caspase-1 compared with nonlesional skin, suggesting its possible role in inflammasome activation in vitiligo. Moreover, the elevated expression of CXCL9 in keratinocytes, mediated through ATP/P2X7 receptor–dependent inflammasome activation, was responsible for CLA+CD8+ T-cell chemotaxis into the skin. These results demonstrate that extracellular ATP as a danger signal activates the inflammasome pathway and increases cutaneous chemotaxis of CD8+ T cells via CXCL9 in vitiligo. Therefore, targeting ATP-P2X7 signaling may be a potential strategy for vitiligo treatment.
Bibliographical noteFunding Information:
This study was supported by a National Research Foundation of Korea grant funded by the Korean government (MSIP) (NRF-2016R1C1B2008015 & NRF-2019R1A2C4069490) and by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute, funded by the Ministry of Health and Welfare , Republic of Korea ( HI18C0262 ). The authors thank Caroline Le Poole for providing PIG1 and PIG3V cell lines. The authors also thank Medical Illustration & Design for providing excellent support with medical illustration (graphic abstract).
© 2020 The Authors
All Science Journal Classification (ASJC) codes
- Molecular Biology
- Cell Biology