Macrophages sense and follow physiologically relevant K+ and Na+ gradients: how induced dipoles and ionotaxis may explain electrotaxis

Many cells respond to changes in concentration of extracellular molecules (chemotaxis) by directing migration towards increased concentration of molecules such as food or signaling molecules, or away from toxins. Similarly, some cells respond to extracellular electric fields by migrating towards cathode or anode (electrotaxis). However, only motile bacteria are known to respond to extracellular ion gradients (ionotaxis), with no similar reports in mammalian cells. We used microfluidic gradient chips to examine the migration of human macrophages in concentration gradients of sodium, potassium and chloride. All three ion gradients significantly directed motion in the direction of the gradient compared to cell migration at constant concentration. Macrophages showed significant migration towards higher concentrations of cations. Gradients as low as ± 0.025% over ambient ion concentration could be sensed. The results suggest that macrophages use small changes in extracellular K + and Na+, to identify injury sites, given that increases in local K+ in the body would signify cell rupture. We also considered the implications of this effect for the phenomenon of electrotaxis. Electric fields induce dipoles at the cell surface, aligned with the field. If these interact with extracellular ions, they will generate local ion gradients across the cell, which the cell can then follow. Hence it is the induced gradient, not the electric field, which the cell interacts with. This work suggests that local variation in ion concentrations may be a previously unexplored mechanism for cellular communication with ramifications for cell function, developmental biology and cancer.