TY - JOUR
T1 - Glycogen synthase kinase 3β promotes liver innate immune activation by restraining AMP-activated protein kinase activation
AU - Zhou, Haoming
AU - Wang, Han
AU - Ni, Ming
AU - Yue, Shi
AU - Xia, Yongxiang
AU - Busuttil, Ronald W.
AU - Kupiec-Weglinski, Jerzy W.
AU - Lu, Ling
AU - Wang, Xuehao
AU - Zhai, Yuan
N1 - Publisher Copyright:
© 2018 European Association for the Study of the Liver
PY - 2018/7
Y1 - 2018/7
N2 - 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.
AB - 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.
KW - AMP-activated protein kinase
KW - Glycogen synthase kinase 3 beta
KW - IL-10
KW - Inflammation
KW - Ischaemia–reperfusion injury
KW - Macrophage
KW - Small heterodimer partner
KW - Toll-like receptor
UR - http://www.scopus.com/inward/record.url?scp=85044734688&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85044734688&partnerID=8YFLogxK
U2 - 10.1016/j.jhep.2018.01.036
DO - 10.1016/j.jhep.2018.01.036
M3 - Article
C2 - 29452207
AN - SCOPUS:85044734688
SN - 0168-8278
VL - 69
SP - 99
EP - 109
JO - Journal of Hepatology
JF - Journal of Hepatology
IS - 1
ER -