Figure 7.

Model for the Cbl–GLUT1 axis-dependent negative regulation of NLRP3 inflammasomes. On the basis of our results, we proposed that Cbl reduces surface expression of GLUT1 protein and thereby contributes to suppression of the NLRP3 inflammasomes. GLUT1 protein encoded by the gene solute carrier family 2 member 1 (SLC2A1) is a major glucose transporter in macrophages that transports glucose from outside to inside cells. Intracellular glucose is an indispensable substrate for initiation of glycolysis. In response to stimulation of the NLRP3 agonist nigericin, glycolysis is activated and fuel oxidative phosphorylation (OXPHOS) activation occurs, which increases the generation of by-products from OXPHOS, known as cellular ROS, which then stimulate NLRP3 inflammasome activation and IL-1β secretion. GLUT1 expression is reduced by Cbl through post-transcriptional regulation. Reduction of GLUT1 by Cbl inhibits the cellular glucose uptake, which thus dampens the NLRP3 inflammasomes. Importantly, inhibition of Cbl with hydrocotarnine can remove the restraints on GLUT1 expression and enhance NLRP3 inflammasome activation.