Highlights
- •Myeloid Gsk3β promotes liver pro-inflammatory immune responses to ischemia reperfusion.
- •Active Gsk3β inhibits AMPK activation and SHP induction in activated macrophages.
- •Gsk3β regulates AMPK/SHP independent of its S9 phosphorylation status.
Background & Aims
Glycogen synthase kinase 3β (Gsk3β [Gsk3b]) is a ubiquitously expressed kinase with distinctive functions in different types
of cells. Although its roles in regulating innate immune activation and ischaemia
and reperfusion injuries (IRIs) have been well documented, the underlying mechanisms
remain ambiguous, in part because of the lack of cell-specific tools in vivo.
Methods
We created a myeloid-specific Gsk3b knockout (KO) strain to study the function of Gsk3β in macrophages in a murine liver
partial warm ischaemia model.
Results
Compared with controls, myeloid Gsk3b KO mice were protected from IRI, with diminished proinflammatory but enhanced anti-inflammatory
immune responses in livers. In bone marrow-derived macrophages, Gsk3β deficiency resulted
in an early reduction of Tnf gene transcription but sustained increase of Il10 gene transcription on Toll-like receptor 4 stimulation in vitro. These effects were associated with enhanced AMP-activated protein kinase (AMPK)
activation, which led to an accelerated and higher level of induction of the novel
innate immune negative regulator small heterodimer partner (SHP [Nr0b2]). The regulatory function of Gsk3β on AMPK activation and SHP induction was confirmed
in wild-type bone marrow-derived macrophages with a Gsk3 inhibitor. Furthermore, we
found that this immune regulatory mechanism was independent of Gsk3β Ser9 phosphorylation
and the phosphoinositide 3-kinase–Akt signalling pathway. In vivo, myeloid Gsk3β deficiency facilitated SHP upregulation by ischaemia–reperfusion in
liver macrophages. Treatment of Gsk3b KO mice with either AMPK inhibitor or SHP small interfering RNA before the onset
of liver ischaemia restored liver proinflammatory immune activation and IRI in these
otherwise protected hosts. Additionally, pharmacological activation of AMPK protected
wild-type mice from liver IRI, with reduced proinflammatory immune activation. Inhibition
of the AMPK–SHP pathway by liver ischaemia was demonstrated in tumour resection patients.
Conclusions
Gsk3β promotes innate proinflammatory immune activation by restraining AMPK activation.
Lay summary
Glycogen synthase kinase 3β promotes macrophage inflammatory activation by inhibiting
the immune regulatory signalling of AMP-activated protein kinase and the induction
of small heterodimer partner. Therefore, therapeutic targeting of glycogen synthase
kinase 3β enhances innate immune regulation and protects liver from ischaemia and
reperfusion injury.
Graphical abstract
Graphical Abstract
Keywords
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Article info
Publication history
Published online: February 13, 2018
Accepted:
January 30,
2018
Received in revised form:
January 8,
2018
Received:
September 26,
2017
Identification
Copyright
© 2018 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
