Kir2.1 channel regulates macrophage polarization via the Ca2+/CaMK II/ERK/NF-κB signaling pathway

Area of Science:

• Immunology
• Cell Biology
• Ion Channel Physiology

Background:

• Macrophage polarization is central to inflammation.
• The role of ion channels in macrophage polarization remains largely unexplored.
• Kir2.1 (KCNJ2) is an inward rectifier potassium channel.

Purpose of the Study:

• To investigate the role of the Kir2.1 channel in macrophage polarization.
• To elucidate the signaling pathways involved in Kir2.1-mediated macrophage polarization.

Main Methods:

• Macrophage polarization assays (M1/M2) with Kir2.1 knockdown or blockade.
• Stimulation with lipopolysaccharide (LPS) in varying extracellular K+ and Ca2+ concentrations.
• Intracellular Ca2+ imaging.
• Western blot analysis of signaling proteins (p-CaMK II, p-ERK, p-NF-κB).
• In vivo mouse model of LPS-induced peritonitis.

Main Results:

• Kir2.1 channel blockade or knockdown inhibited M1 polarization and promoted M2 polarization.
• High extracellular K+ (70 mM) suppressed LPS-induced M1 polarization, an effect partially reversed by Ca2+.
• Ca2+ influx was dependent on Kir2.1-generated hyperpolarized membrane potential.
• Kir2.1 blockade or high K+ medium reversed LPS-induced upregulation of p-CaMK II, p-ERK, and p-NF-κB.
• Kir2.1 channel blocker treatment protected mice from LPS-induced peritonitis.

Conclusions:

• The Kir2.1 channel is essential for M1 macrophage polarization.
• Kir2.1 regulates macrophage polarization through the Ca2+/CaMK II/ERK/NF-κB signaling pathway.
• Targeting the Kir2.1 channel may be a viable strategy for modulating inflammatory responses.