*Purpose: We have shown previously that glycogen synthase kinase β (Gsk3β) regulates liver inflammatory activation against ischemia/reperfusion injury (IRI). The question of whether it also plays a role in the inflammation resolution and the restoration of tissue homeostasis post IR has not been properly addressed. As the dominant innate immune cells in livers, macrophages are heterogenous. Whether Gsk3β differentially regulates resident vs. infiltrating types of tissue macrophages at different stages of the inflammatory response remains to be determined.

*Methods: In a murine liver partial warm ischemia (90m) reperfusion injury (IRI) model, we compared myeloid-specific Gsk3b KO mice and their controls in the pathogenesis of liver IRI at both the activation and resolution stage (6h and day 3-7 post reperfusion). Kupffer cells were selectively depleted by low dose of clodronate liposomes. Bone marrow-derived macrophages were used to reconstitute diphtheria toxin-treated CD11b-DTR mice.

*Results: Gsk3β inhibitory phosphorylation at serine 9 was increased in IR livers at both the activation and resolution stages of the disease process. Myeloid Gsk3β deficiency not only reduced hepatocellular damages at 6h, but also facilitated the resolution of liver IRI (at day 3 vs. day 7 in WT mice post reperfusion). This was demonstrated at the recovery of tissue injury (histology) /inflammatory gene expression (qRT-PCR), as well as the clearance/reprogramming of infiltrating neutrophils/macrophages (FACS). Treatments of mice with anti-IL-10 Ab- or clodronate liposomes prior to the onset of liver ischemia diminished the differences in the severities of liver injuries at 6h post reperfusion between WT and the KO mice. However, the resolution of liver IRI remained accelerated in these treated KO mice. The reconstitution of CD11b-DTR mice with Gsk3β deficient bone marrow-derived macrophages (BMMs) facilitated the resolution of liver IRI, as compared with those with WT cells. At the cellular level, Gsk3β deficiency promoted MerTK induction in liver infiltrating macrophages in vivo and in LXR-stimulated BMMs in vitro. Gsk3 pharmacological inhibition facilitated the resolution of liver IRI in WT, but not myeloid MerTK KO, mice.

*Conclusions: Gsk3β regulates the resolution of liver IRI independent of its roles in the activation stage of the disease. Gsk3 inactivation promotes the pro-resolution function in liver infiltrating macrophages by facilitating MerTK induction.

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