Gsk3β regulates the resolution of liver ischemia/reperfusion injury via MerTK.
Gsk3β regulates the resolution of liver ischemia/reperfusion injury via MerTK.
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Gsk 3 β通过MerTK调节肝脏缺血/再灌注损伤的消退
DOI：
10.1172/jci.insight.151819
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发表时间：
2023-01-10
期刊：
影响因子：
8
通讯作者：
Zhai, Yuan
中科院分区：
文献类型：
--
作者：
Zhang, Hanwen;Ni, Ming;Wang, Han;Zhang, Jing;Jin, Dan;Busuttil, Ronald W.;Kupiec-Weglinski, Jerzy W.;Li, Wei;Wang, Xuehao;Zhai, Yuan
尽管糖原合成酶激酶β（Gsk3β）已被证明可调节组织炎症，但它是否以及如何调节炎症消退与炎症激活尚不明确。在小鼠肝脏局部温缺血/再灌注损伤（IRI）模型中，我们发现Gsk3β的抑制性磷酸化在疾病的早期激活和晚期消退阶段均增加。髓系Gsk3β缺失不仅减轻了肝脏损伤，还促进了肝脏内稳态的恢复。在肝脏缺血发生前清除枯否细胞可减弱野生型（WT）和Gsk3β敲除（KO）小鼠在肝脏IRI激活方面的差异。然而，肝脏IRI的消退在Gsk3β - KO小鼠中仍然加速。在CD11b - DTR小鼠中，与野生型细胞相比，Gsk3β缺陷的骨髓来源巨噬细胞（BMMs）促进了肝脏IRI的消退。此外，Gsk3β缺失促进了肝脏浸润巨噬细胞在体内以及BMMs在体外的修复表型分化。Gsk3的药理抑制促进了野生型小鼠肝脏IRI的消退，但在髓系MerTK缺陷小鼠中则无此作用。因此，Gsk3β在疾病的激活和消退阶段均调节肝脏IRI。Gsk3失活以MerTK依赖的方式增强肝脏浸润巨噬细胞的促消退功能。
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.
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糖原合成酶激酶 3 N 端丝氨酸磷酸化在肝缺血再灌注损伤中的亚型和细胞类型特异性作用
DOI：
10.4049/jimmunol.2000397
发表时间：
2020-08-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Ni M;Zhou H;Zhang J;Jin D;Lu T;Busuttil RW;Kupiec-Weglinski JW;Wang X;Zhai Y
通讯作者：
Zhai Y
影响因子：
13.5
作者：
Llacuna, Laura;Barcena, Cristina;Bellido-Martin, Lola;Fernandez, Laura;Stefanovic, Milica;Mari, Montserrat;Garcia-Ruiz, Carmen;Fernandez-Checa, Jose C.;Garcia de Frutos, Pablo;Morales, Albert
通讯作者：
Morales, Albert
影响因子：
13.5
作者：
Bamboat, Zubin M.;Balachandran, Vinod P.;Ocuin, Lee M.;Obaid, Hebroon;Plitas, George;DeMatteo, Ronald P.
通讯作者：
DeMatteo, Ronald P.
影响因子：
4.6
作者：
Kim SY;Lim EJ;Yoon YS;Ahn YH;Park EM;Kim HS;Kang JL
通讯作者：
Kang JL
DOI：
10.1084/jem.20141539
发表时间：
2015-04-06
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Dal-Secco D;Wang J;Zeng Z;Kolaczkowska E;Wong CH;Petri B;Ransohoff RM;Charo IF;Jenne CN;Kubes P
通讯作者：
Kubes P