Effects of E-LXA4 on Kv and Kir Recorded from Bone Marrow Mouse Macrophages

Abstract

Macrophages may tune the immune response toward inflammation or tolerance. The proliferation, activation, and resolution or tolerance of immune cells is mainly modulated by membrane transduction of extracellular signals. Some of these interactions involve changes in transmembrane ion fluxes that, in turn, modulate the network of intracellular signaling. Potassium channels modulate macrophage physiology. Blockade of voltage dependent potassium channels (Kv) by specific antagonists decreases macrophage cytokine production and inhibits proliferation. Therefore, Kv channels have been proposed as anti-inflammatory targets. We studied the effects of 15-epi-lipoxin (e-LXA4), an endogenous eicosanoid released in the presence of aspirin on early signaling and on voltage-dependent potassium (Kv: Kv1.3, Kv1.5) and inward rectifier potassium channels (Kir) in mice bone marrow-derived macrophages (BMDM) and in cultured HEK293 cells. Electrophysiological experiments recordings were performed by the whole-cell patch-clamp technique. Treatment of BMDM with e-LXA4 inhibited LPS-dependent activation of NF-κB and IKKβ activity and protected against LPS activation-dependent apoptosis. Acute treatment of LPS-stimulated BMDM with e-LXA4 resulted in a decrease of Kv currents, compatible with attenuation of the inflammatory response. More importantly, long-term treatment of LPS-stimulated BMDM with e-LXA4 significantly reverted LPS effects on Kv and Kir currents. These effects were partially mediated via the lipoxin receptor (ALX), since were partially reverted in the presence of a selective ALX receptor antagonist. In the present work, we provide evidence for a new mechanism by which e-LXA4 contributes to inflammation resolution consisting in the reversion of LPS effects on Kv and Kir currents in macrophages. In fact, the lack of effects on Kv and Kir currents recorded in HEK293 cells demonstrated that an intracellular signaling network is required to produce the effect observed in BMDM on the LPS-dependent activation with e-LXA4. Granted by SAF2010-14916 and FIS-RIC RD12/0042/0019.