Gsk3β regulates the resolution of liver ischemia/reperfusion injury via MerTK

Although glycogen synthase kinase beta (Gsk3 beta) has been shown to regulate tissue inflammation, whether and how it regulates inflammation resolution versus inflammation activation is unclear. In a murine liver, partial warm ischemia/reperfusion injury (IRI) model, we found that Gsk3 beta inhibitory phosphorylation increased at both the early-activation and late-resolution stages of the disease. Myeloid Gsk3 beta deficiency not only alleviated liver injuries, it also facilitated the restoration of liver homeostasis. Depletion of Kupffer cells prior to the onset of liver ischemia diminished the differences between the WT and Gsk3 beta-KO mice in the activation of liver IRI. However, the resolution of liver IRI remained accelerated in Gsk3 beta-KO mice. In CD11b-DTR mice, Gsk3 beta-deficient BM-derived macrophages (BMMs) facilitated the resolution of liver IRI as compared with WT cells. Furthermore, Gsk3 beta deficiency promoted the reparative phenotype differentiation in vivo in liver-infiltrating macrophages and in vitro in BMMs. Gsk3 pharmacological inhibition promoted the resolution of liver IRI in WT, but not myeloid MerTK-deficient, mice. Thus, Gsk3 beta regulates liver IRI at both activation and resolution stages of the disease. Gsk3 inactivation enhances the proresolving function of liver-infiltrating macrophages in an MerTK-dependent manner.