WNK1-TAK1 signaling suppresses lipopolysaccharide-induced cytokine production and classical activation in macrophages
WNK1-TAK1 signaling suppresses lipopolysaccharide-induced cytokine production and classical activation in macrophages
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DOI：
10.1016/j.bbrc.2020.10.007
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发表时间：
2020-12-17
影响因子：
3.1
通讯作者：
Sohara, Eisei
中科院分区：
文献类型：
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作者：
Arai, Yohei;Asano, Kenichi;Sohara, Eisei
无赖氨酸激酶（WNK）在调节电解质稳态、细胞信号传导、存活和增殖等方面发挥着重要作用。最近有研究表明，WNK家族成员WNK1可以改变免疫细胞的功能。在巨噬细胞中，WNK1通过tgfb活化激酶1 （TAK1）介导的核因子- κ B （nf - κ B）和丝裂原活化蛋白激酶（MAPK）信号通路的激活，对脂多糖（LPS）诱导的炎症反应具有抑制作用。我们发现，在lps诱导的实验性脓毒症模型中，WNK1杂合子（WNK1(+/-)）小鼠产生过多的促炎细胞因子，并且从WNK1（+/-）小鼠分离的腹腔巨噬细胞产生更高水平的lps诱导的细胞因子和NOS2表达，作为典型的促炎M1巨噬细胞标志物。我们证实，小发卡RNA （shRNA）介导的WNK1敲低激活了lps诱导的RAW 264.7巨噬细胞的细胞因子产生和NOS2表达。此外，我们证明了WNK1敲低增加了NF-kappa B的核转位，激活了p38和Jun n -末端激酶（JNK） MAPK信号通路，TAK1抑制剂减弱了WNK1敲低的这些作用。这些结果表明WNK1通过与TAK1的相互作用作为生理性免疫调节剂。WNK1可能是对抗脓毒症引起的细胞因子风暴的治疗靶点。(C) 2020爱思唯尔公司版权所有。
With-no-lysine kinase (WNK) plays important roles in regulating electrolyte homeostasis, cell signaling, survival, and proliferation. It has been recently demonstrated that WNK1, a member of the WNK family, modifies the function of immune cells. Here we report that in macrophages, WNK1 has suppressive effects on lipopolysaccharide (LPS)-induced inflammatory responses via TGFB-activated kinase 1 (TAK1)mediated activation of nuclear factor-kappa B (NF-kappa B) and mitogen-activated protein kinase (MAPK) signaling pathway. We found that WNK1 heterozygous (WNK1(+/-)) mice produced excessive proinflammatory cytokines in an experimental LPS-induced sepsis model, and peritoneal macrophages isolated from WNK1(+/-) mice produced higher levels of LPS-induced cytokines and NOS2 expression as canonical proinflammatory M1 macrophage markers. We confirmed that small hairpin RNA (shRNA)mediated knockdown of WNK1 activated LPS-induced cytokine production and NOS2 expression in RAW 264.7 macrophages. Moreover, we demonstrated that WNK1 knockdown increased the nuclear trans location of NF-kappa B and activated the p38 and Jun N-terminal kinase (JNK) MAPK signaling pathway and that a TAK1 inhibitor diminished these effects of WNK1 knockdown. These results suggest that WNK1 acts as a physiologic immune modulator via interactions with TAK1. WNK1 may be a therapeutic target against the cytokine storm caused by sepsis. (C) 2020 Elsevier Inc. All rights reserved.