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Updated: Aug 20, 2025
Use of a Hanging-weight System for Liver Ischemia in Mice
Published on: August 7, 2012
Gsk3β regulates the resolution of liver ischemia/reperfusion injury via MerTK
Hanwen Zhang1,2, Ming Ni1,3, Han Wang1,3
1Dumont-UCLA Transplant Center, Department of Surgery, David Geffen School of Medicine, UCLA, Los Angeles, California, USA.
Abstract:
Although glycogen synthase kinase β (Gsk3β) 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 Gsk3β inhibitory phosphorylation increased at both the early-activation and late-resolution stages of the disease. Myeloid Gsk3β 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 Gsk3β-KO mice in the activation of liver IRI. However, the resolution of liver IRI remained accelerated in Gsk3β-KO mice. In CD11b-DTR mice, Gsk3β-deficient BM-derived macrophages (BMMs) facilitated the resolution of liver IRI as compared with WT cells. Furthermore, Gsk3β 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, Gsk3β 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.
Insights
Glycogen synthase kinase β (Gsk3β) plays a dual role in liver injury, impacting both inflammation and its resolution. Inhibiting Gsk3β in myeloid cells accelerates liver injury repair by enhancing macrophage proresolving functions.
Area of Science:
- Immunology
- Cell Biology
- Hepatology
Background:
- Glycogen synthase kinase β (Gsk3β) is implicated in tissue inflammation, but its specific roles in inflammation activation versus resolution remain unclear.
- Understanding Gsk3β's function in liver injury is crucial for developing targeted therapies.
Purpose of the Study:
- To investigate the role of Gsk3β in regulating inflammation activation and resolution during liver ischemia/reperfusion injury (IRI).
- To determine whether Gsk3β deficiency or inhibition impacts liver injury outcomes and macrophage function.
Main Methods:
- Utilized a murine model of partial warm liver IRI.
- Employing myeloid-specific Gsk3β knockout (KO) mice and pharmacological Gsk3 inhibition.
- Investigated the role of Kupffer cells and bone marrow-derived macrophages (BMMs) in liver IRI.
- Assessed macrophage phenotype differentiation in vitro and in vivo.
- Examined the involvement of MerTK in Gsk3β's proresolving effects.
Main Results:
- Myeloid Gsk3β deficiency alleviated liver injury and accelerated homeostasis restoration.
- Gsk3β deficiency primarily impacted the resolution phase of liver IRI, not the initial activation, when Kupffer cells were depleted.
- Gsk3β-deficient BMMs enhanced liver IRI resolution compared to wild-type cells.
- Gsk3β deficiency promoted a reparative macrophage phenotype.
- Pharmacological Gsk3 inhibition promoted liver IRI resolution in a MerTK-dependent manner.
Conclusions:
- Gsk3β regulates both the activation and resolution phases of liver IRI.
- Inactivating Gsk3β enhances the proresolving functions of liver-infiltrating macrophages, particularly in a MerTK-dependent pathway.
- Targeting Gsk3β may represent a therapeutic strategy to promote liver injury resolution.
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