Inhibition of NLRP3 inflammasome by MCC950 improves the metabolic outcome of islet transplantation by suppressing IL-1β and islet cellular death

Abstract

AbstractEarly rejection is a critical issue to be overcome to achieve successful islet transplantation. NLRP3 inflammasome is a protein complex that mediates the maturation of pro-interleukin (IL)-1β and pro-IL-18 to IL-1β and IL-18, respectively, which induce cellular death. Here, we investigated the impact of NLRP3 inflammasome and the effect of its inhibition by MCC950 in a rodent model of islet transplantation. We assessed the therapeutic effects of MCC950, a specific inhibitor of NLRP3 inflammasome, on gene expression, islet survival ratio and viability, and islet transplantation in mice. NLRP3 inflammasome-related gene (Nlrp3 and Il1b) expression was upregulated in islets stimulated with proinflammatory cytokines and suppressed when incubated with MCC950. Survival ratio and viability of incubated islets were reduced by cytokine stimulation and improved by MCC950. Regarding islet transplantation, the number of apoptotic cells in transplanted islets was reduced by MCC950. Furthermore, the expression of IL-1β in transplanted islets, migration of macrophages around islets, and fluctuation of blood glucose levels were suppressed by MCC950. Our study revealed that NLRP3 inflammasome worsened the therapeutic outcomes of islet transplantation and that MCC950 administration improved glycaemic control in syngeneic mice that underwent islet transplantation by inhibiting inflammation, which suppressed islet death.