Regulation of methylglyoxal-elicited leukocyte recruitment by endothelial SGK1/GSK3 signaling.

Abstract Excessive levels of the glycolysis metabolite methylglyoxal (MG) elicit enhanced expression of adhesion molecules which foster leukocyte–endothelial cell interactions. The signaling mechanisms involved remain elusive. To address this, we investigated the signal transduction of leukocyte- and endothelial-expressed phosphoinositide 3-kinase (PI3K) effector kinases glycogen synthase kinase 3 (GSK3) and serum- and glucocorticoid-inducible kinase 1 (SGK1) in the regulation of MG-elicited leukocyte recruitment. Using intravital microscopy of mouse cremasteric microvasculature, we demonstrate that GSK3 inhibitors lithium and SB216763 mitigate MG-elicited leukocyte recruitment and microvascular hyperpermeability. In SVEC4-10EE2 endothelial cells, but not in neutrophils, MG transiently activates GSK3 by reducing inhibitory phospho-GSK3α/β (Ser21/9) which parallels decrease of phospho-Akt at early time points ( in vivo to inflammation, thus, unraveling potential therapeutic targets.