Extracellular ATP Activates the NLRP3 Inflammasome and Is an Early Danger Signal of Skin Allograft Rejection

Immune cells are equipped with a number of recep- tors that recognize sterile injury and pathogens. We find that host immune cells release ATP as an inflam- matory signal in response to allogeneic transplanta- tion. ATP then acts via a feedback mechanism on the P2X7 channel to activate the NLRP3 inflamma- some and subsequently process and release inter- leukin (IL)-18. This process is a necessary stage in the deleterious Th1 response against allotransplan- tation via interferon-g production. Lack of IL-18 resulted in a decrease in graft-infiltrating CD8 cells but an increase in regulatory T cells. In human liver transplant patients undergoing progressive immuno- suppressive drug withdrawal, we found that patients experiencing acute rejection had higher levels of the P2X7 receptor in circulating inflammatory mono- cytes compared to tolerant patients. These data suggest that the pharmacological inhibition of the P2X7 receptor or the NLRP3 inflammasome will aid in inducing transplant tolerance without complete immunoparalysis.