Background & Aims: Glycogen synthase kinase 3β (Gsk3β) is ubiquitously expressed with distinctive functions in different types of cells. Although its roles in regulating innate immune activation and the development of ischemia and reperfusion injury (IRI) have been well documented, underlying mechanisms remain ambiguous. Moreover, whether Gsk3ß also regulates inflammation resolution and restoration of tissue homeostasis after IRI remains unknown.

Methods: Myeloid-specific Gsk3β KO strain was used to study its function in macrophages at both early and late stages of tissue inflammation in a murine liver partial warm ischemia model.

Results: Compared with controls, myeloid Gsk3ß KO mice were not only protected from liver IRI, but also recovered more quickly. Peak hepatocellular injury after 90min ischemia was significantly lower (at 6h post reperfusion); and liver homeostasis was restored much earlier after reperfusion (7d in WT vs. 3d in KO at both histological and cellular levels). In bone marrow-derived macrophages (BMMs), Gsk3β deficiency resulted in an early reduction of TNF-a, but sustained increase of IL-10 gene expression upon TLR4 stimulation. Additionally, expression of efferocytosis receptor MerTK and TIM-4, two key molecules for macrophage functions in inflammation resolution, were selectively upregulated in activated KO, but not WT, cells. Intracellular signaling pathway analysis revealed that TLR4 stimulation inhibited AMPK activity early in WT BMMs. Gsk3β deficiency reversed this inhibition, leading to early and higher levels of AMPK activation in stimulated KO cells. This resulted in the induction of the novel innate immune negative regulator small heterodimer partner (SHP). The Gsk3β regulation of AMPK/SHP was confirmed in WT BMMs using Gsk3 chemical inhibitor, and found to be independent of the PI3K-AKT signaling pathway. Treatment of Gsk3β KO mice with either AMPK inhibitor or SHP siRNA prior to the onset of liver ischemia restored cardinal features of liver IRI. In WT mice, on the other hand, pharmacological activation of AMPK protected livers from IRI. AMPK inhibition, although not increasing peak liver IRI (6h post reperfusion), interfered with the restoration of liver homeostasis.

Conclusion: Gsk3β regulates liver inflammation activation and resolution in IRI by restraining AMPK activation.

CITATION INFORMATION: Wang H., Ni M., Zhou H., Lu L., Busuttil R., Kupiec-Weglinski J., Zhai Y. Glycogen Synthase Kinase 3 beta Regulates Liver Inflammation Activation and Resolution by Controlling AMPK Activities Am J Transplant. 2017;17 (suppl 3).

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