Enhancement of neuronal outward delayed rectifier K+ current by human monocyte-derived macrophages

Macrophages are critical cells in mediating the pathology of neurodegenerative disorders and enhancement of neuronal outward potassium (K+) current has implicated in neuronal apoptosis. To understand how activated macrophages induce neuronal dysfunction and injury, we studied the effects of lipopolysaccharide (LPS)-stimulated human monocytes-derived macrophage (MDM) on neuronal outward delayed rectifier K+ current (I_K) and resultant change on neuronal viability in primary rat hippocampal neuronal culture. Bath application of LPS-stimulated MDM-conditioned media (MCM) enhanced neuronal IK in a concentration-dependent manner, whereas non-stimulated MCM failed to alter neuronal I_K. The enhancement of neuronal I_K was repeated in a macrophage-neuronal co-culture system. The link of stimulated MCM (MCM(+))-associated enhancement of I_K to MCM(+)-induced neuronal injury, as detected by PI/DAPI (propidium iodide/4′,6-diamidino-2- phenylindol) staining and MTT assay, was demonstrated by experimental results showing that addition of I_K blocker tetraethylammonium to the culture protected hippocampal neurons from MCM(+)-associated challenge. Further investigation revealed elevated levels of K_v 1.3 and K_v 1.5 channel expression in hippocampal neurons after addition of MCM(+) to the culture. These results suggest that during brain inflammation macrophages, through their capacity of releasing bioactive molecules, induce neuronal injury by enhancing neuronal I_K and that modulation of K_v channels is a new approach to neuroprotection.