Effects of electrical stimulation on cytokine-induced macrophage polarization

Macrophages have two functionalized phenotypes, M1 and M2, and the regulation of M1/M2 polarization of macrophages is critical for tissue repair. Tissue-derived immune factors are considered the major drivers of macrophage polarization. Based on the main cytokine-induced polarization pathways, we tested the effect of electrical stimulation (ES) of macrophages on the regulation of M1/M2 polarization and a possible synergistic effect with the cytokines. Indium tin oxide (ITO) planar microelectrodes were used to produce ES under different voltages, frequencies and waveforms. We evaluated the influence of ES on the cytokine-induced M1/M2 polarization using mouse bone marrow-derived macrophages cultured with both lipopolysaccharide (LPS)/IFN-γ factors and IL-4 factors for M1 and M2, respectively. The results showed that ES promoted the cytokine-induced macrophage polarization. Importantly, we found that stimulation with a square waveform selectively promoted LPS/IFN-γ-induced M1 polarization, while stimulation with a sinusoidal waveform promoted both LPS/IFN-γ-induced M1, and IL-4-induced M2 polarization. Mechanistically, stimulation with a square waveform affected the intracellular ion concentration, whereas stimulation with a sinusoidal waveform promoted both the intracellular ion concentration and membrane receptors. We hereby establish an ES-mediated strategy for immunomodulation via macrophage polarization.