Macrophage polarization plays a key role in inflammatory response. Various ion channels expressed in macrophages has been documented, but very little is known about their roles in macrophage polarization. We find that knockdown or blockade of Kir2.1 channel significantly inhibits M1 polarization, but promotes M2 polarization. LPS induced M1 polarization is also remarkably suppressed in high extracellular K+ solutions (70 mM K+), and this inhibition is partially abolished by adding Ca2+ in the culture medium. Calcium imaging shows that Ca2+ influx is dependent on the hyperpolarized membrane potential generated by Kir2.1 channel. The upregulation of p-CaMK II, p-ERK1/2, and p-NF-κB proteins in RAW264.7 macrophages stimulated with LPS are significantly reversed by blocking Kir2.1 channel or culturing the cells with 70 mM K+ medium. Furthermore, in vivo study shows that mice treated with Kir2.1 channel blocker are protected from LPS-induced peritonitis. In summary, our data reveal the essential role of Kir2.1 channel in regulating macrophage polarization via Ca2+ / CaMK II / ERK1/2 / NF-κB pathway.

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