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WNK4-SPAK modulates lipopolysaccharide-induced macrophage activation.
WNK4-SPAK 调节脂多糖诱导的巨噬细胞活化。
- 影响因子:4.42
- DOI:10.1016/j.bcp.2019.113738
- 作者列表:"Hung CM","Peng CK","Yang SS","Shui HA","Huang KL
- 发表时间:2020-01-01
Abstract
:Dysregulation of alveolar macrophage activation has been recognized as the major mechanism in the pathogenesis of acute lung injury. The aim of the present study was to investigate the role of NKCC1 regulating mechanism in modulating macrophage activation. Knockout (SPAK-/- and WNK4-/-) and knockin (WNK4D561A/+) mice were used in this study. LPS induced expression of p-NKCC1 and activation of NFκB in the primary culture of alveolar macrophages. WNK4 or SPAK knockout suppressed p-NKCC1 expression and inflammation cascade activation, whereas WNK4 knockin enhanced these responses. Intrapulmonary administration of LPS induced in vivo expression and phosphorylation of NKCC1 in alveolar inflammation cells and caused a shift in the cell population from macrophage to neutrophil predominance. WNK4 or SPAK knockout attenuated the LPS-induced alveolar cell-population shifting, macrophage NKCC1 phosphorylation, and acute lung injury, whereas WNK4 knockin augmented the inflammatory response. In summary, our results demonstrated the presence of NKCC1 in alveolar macrophage, which is inducible by lipopolysaccharide. Our results also showed showed that the WNK4-SPAK-NKCC1 cascade plays an important role in modulating macrophage activation to regulate LPS-induced lung inflammation and lung injury.
摘要
肺泡巨噬细胞活化失调已被认为是急性肺损伤发病的主要机制。本研究的目的是探讨 NKCC1 调节机制在调节巨噬细胞活化中的作用。本研究采用基因敲除 (SPAK-/-和 WNK4-/-) 和基因敲除 (WNK4D561A/+) 小鼠。LPS 诱导肺泡巨噬细胞原代培养 p-NKCC1 表达及 nf κ b 活化WNK4 或 SPAK 敲除抑制 p-NKCC1 表达和炎症级联激活,而 WNK4 敲除增强了这些反应。肺内给予 LPS 诱导肺泡炎症细胞中 NKCC1 的体内表达和磷酸化,并引起细胞群从巨噬细胞向中性粒细胞为主的转变。WNK4 或 SPAK 敲除可减弱 LPS 诱导的肺泡细胞群转移、巨噬细胞 NKCC1 磷酸化和急性肺损伤,而 WNK4 敲除可增强炎症反应。总之,我们的结果证明了肺泡巨噬细胞中 NKCC1 的存在,它是由脂多糖诱导的。我们的研究结果还表明,WNK4-SPAK-NKCC1 级联反应在调节巨噬细胞活化以调节 LPS 诱导的肺部炎症和肺损伤中起重要作用。
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