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

Abstract

Summary: Immune cells are equipped with a number of receptors that recognize sterile injury and pathogens. We find that host immune cells release ATP as an inflammatory signal in response to allogeneic transplantation. ATP then acts via a feedback mechanism on the P2X7 channel to activate the NLRP3 inflammasome and subsequently process and release interleukin (IL)-18. This process is a necessary stage in the deleterious Th1 response against allotransplantation via interferon-γ 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 immunosuppressive drug withdrawal, we found that patients experiencing acute rejection had higher levels of the P2X7 receptor in circulating inflammatory monocytes 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. : Amores-Iniesta et al. find that extracellular ATP is important in the establishment of allograft rejection during mismatched tissue transplantation through NLRP3 inflammasome activation and IL-18 production. The P2X7 receptor in macrophages helps to maintain high extracellular ATP levels in mismatched tissue grafts at early time points after transplantation. Keywords: allotransplantation, caspase-1, IL-18, macrophages, NLRP3 inflammasome, P2X7 receptor, skin transplant, purinergic signaling, ATP release, danger signal