J. Immunol. 191, 6136–6146 (2013)

Macrophage cells are central players in the immune system and can be activated by different stimuli, resulting in two different downstream pathways. The innate activation pathway results from stimulation by pathogen lipopolysaccharide (LPS), whereas the second alternative pathway is activated by various cytokines and glucocorticoids. Voltage-dependent potassium channels (Kv) are regulated by both pathways but in opposite directions: the innate pathway triggers Kv outward current, whereas alternative activation downregulates Kv current. Also, innate activation increases, whereas alternative activation decreases, the ratio of the Kv1.3 to Kv1.5 isoforms in these cells. To explore the connections between the two types of activation and the role of potassium channels, Moreno et al. monitored the responses in bone marrow–derived macrophages to the endogenous anti-inflammatory eicosanoids 15-epi-LXA4 (e-LXA4) and the less potent lipoxin A4 (LXA4), which have been shown to inhibit the alternative activation pathway via their receptor ALX. e-LXA4 acted on Kv channels to generate inactivating currents and led to inhibition of the pro-inflammatory transcription factor NF-κB via modulation of its activator IKKβ. e-LXA4 also prevented changes in Kv1.3/Kv1.5 stoichiometry through changes in the innate LPS signaling pathway that specifically involve ALX receptors that then modulate Kv1.3 channels. These results suggest that the anti-inflammatory action of e-LXA4 results from attenuating NF-kB and additionally by modulating potassium currents in macrophages.