Kir2.1 channel regulates macrophage polarization via the Ca2+/CaMK II/ERK/NF-κB signaling pathway
Kir2.1 channel regulates macrophage polarization via the Ca2+/CaMK II/ERK/NF-κB signaling pathway
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Kir2.1 通道通过 Ca2 /CaMK II/ERK/NF-κB 信号通路调节巨噬细胞极化
DOI：
10.1242/jcs.259544
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发表时间：
2022-07-01
影响因子：
4
通讯作者：
Gao, Zhe
中科院分区：
文献类型：
--
作者：
Chen, Kuihao;Man, Qiaoyan;Gao, Zhe
巨噬细胞极化在炎症反应中起关键作用。巨噬细胞中表达的各种离子通道已被记录，但对它们在巨噬细胞极化中的作用知之甚少。我们发现，敲低或阻断Kir2.1（也称为KCNJ 2）通道显着抑制M1巨噬细胞极化，但促进M2巨噬细胞极化。脂多糖（LPS）诱导的M1极化也显着抑制在高细胞外K+溶液（70 mM K+），这种抑制被部分废除，通过添加Ca 2+的培养基。Ca ~（2+）显像显示Ca ~（2+）内流依赖于Kir2.1通道产生的超极化膜电位。通过阻断Kir2.1通道或用70 mM K+培养基培养细胞，LPS刺激的来自RAW 264.7细胞系的巨噬细胞中磷酸（p）-CaMK II、p-ERK和p-NF-κ B蛋白的上调被显著逆转。此外，体内研究表明，用Kir2.1通道阻断剂治疗的小鼠受到保护，免受LPS诱导的腹膜炎。总之，我们的数据揭示了Kir2.1通道通过Ca 2 +/CaMK II/ERK/NF-κ B信号通路在调节巨噬细胞极化中的重要作用。
Macrophage polarization plays a key role in the inflammatory response. Various ion channels expressed in macrophages have been documented, but very little is known about their roles in macrophage polarization. We found that knockdown or blockade of the Kir2.1 (also known as KCNJ2) channel significantly inhibited M1 macrophage polarization, but promoted M2 macrophage polarization. Lipopolysaccharide (LPS)-induced M1 polarization was also remarkably suppressed in high extracellular K+ solutions (70 mM K+), and this inhibition was partially abolished by adding Ca2+ to the culture medium. Ca2+ imaging showed that Ca2+ influx was dependent on the hyperpolarized membrane potential generated by the Kir2.1 channel. The upregulation of phospho (p)-CaMK II, p-ERK, and p-NF-kappa B proteins in macrophages from the RAW264.7 cell line that were stimulated with LPS was significantly reversed by blocking the Kir2.1 channel or culturing the cells with 70 mM K+ medium. Furthermore, in vivo studies showed that mice treated with a Kir2.1 channel blocker were protected from LPS-induced peritonitis. In summary, our data reveal the essential role of the Kir2.1 channel in regulating macrophage polarization via the Ca2+/CaMK II/ERK/NF-kappa B signaling pathway.