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Modulation of voltage-dependent and inward rectifier potassium channels by 15-epi-lipoxin-A4 in activated murine
Cristina Moreno1, Patricia Prieto, Álvaro Macías
1Instituto de Investigaciones Biomédicas "Alberto Sols," Consejo Superior de Investigaciones Cientificas, Universidad Autónoma de Madrid, 28029 Madrid, Spain.
Abstract:
Potassium channels modulate macrophage physiology. Blockade of voltage-dependent potassium channels (Kv) by specific antagonists decreases macrophage cytokine production and inhibits proliferation. In the presence of aspirin, acetylated cyclooxygenase-2 loses the activity required to synthesize PGs but maintains the oxygenase activity to produce 15R-HETE from arachidonate. This intermediate product is transformed via 5-LOX into epimeric lipoxins, termed 15-epi-lipoxins (15-epi-lipoxin A4 [e-LXA4]). Kv have been proposed as anti-inflammatory targets. Therefore, we studied the effects of e-LXA4 on signaling and on Kv and inward rectifier potassium channels (Kir) in mice bone marrow-derived macrophages (BMDM). Electrophysiological recordings were performed in these cells by the whole-cell patch-clamp technique. Treatment of BMDM with e-LXA4 inhibited LPS-dependent activation of NF-κB and IκB kinase β activity, protected against LPS activation-dependent apoptosis, and enhanced the accumulation of the Nrf-2 transcription factor. Moreover, treatment of LPS-stimulated BMDM with e-LXA4 resulted in a rapid decrease of Kv currents, compatible with attenuation of the inflammatory response. Long-term treatment of LPS-stimulated BMDM with e-LXA4 significantly reverted LPS effects on Kv and Kir currents. Under these conditions, e-LXA4 decreased the calcium influx versus that observed in LPS-stimulated BMDM. These effects were partially mediated via the lipoxin receptor (ALX), because they were significantly reverted by a selective ALX receptor antagonist. We provide evidence for a new mechanism by which e-LXA4 contributes to inflammation resolution, consisting of the reversion of LPS effects on Kv and Kir currents in macrophages.
Insights
15-epi-lipoxin A4 (e-LXA4) resolves inflammation by modulating macrophage potassium channels. This novel mechanism targets voltage-dependent (Kv) and inward rectifier (Kir) channels, reducing inflammatory responses and promoting resolution.
Area of Science:
- Immunology
- Cell Physiology
- Pharmacology
Background:
- Potassium channels (Kv) are crucial for macrophage function, influencing cytokine production and proliferation.
- Aspirin metabolism generates 15-epi-lipoxins (e.g., 15-epi-lipoxin A4), which have potential anti-inflammatory roles.
- Kv channels are emerging as therapeutic targets for managing inflammatory conditions.
Purpose of the Study:
- To investigate the effects of 15-epi-lipoxin A4 (e-LXA4) on potassium channels (Kv and Kir) and inflammatory signaling in macrophages.
- To elucidate the role of e-LXA4 in modulating macrophage responses to lipopolysaccharide (LPS).
- To explore the potential of e-LXA4 as an inflammation resolution mediator.
Main Methods:
- Whole-cell patch-clamp electrophysiology was used to record potassium channel activity in mouse bone marrow-derived macrophages (BMDM).
- BMDM were treated with e-LXA4 and/or LPS to assess effects on cellular signaling pathways (NF-κB, IκB kinase β, Nrf-2) and apoptosis.
- The involvement of the lipoxin receptor (ALX) was evaluated using a selective ALX receptor antagonist.
Main Results:
- e-LXA4 inhibited LPS-induced NF-κB activation and IκB kinase β activity, while protecting against apoptosis and enhancing Nrf-2 accumulation.
- Treatment with e-LXA4 rapidly decreased Kv currents in LPS-stimulated BMDM, suggesting an anti-inflammatory effect.
- Long-term e-LXA4 treatment reversed LPS-induced alterations in both Kv and Kir currents, reduced calcium influx, and these effects were partially ALX receptor-dependent.
Conclusions:
- 15-epi-lipoxin A4 (e-LXA4) demonstrates significant anti-inflammatory properties by modulating macrophage potassium channel activity.
- e-LXA4 resolves inflammation through a novel mechanism involving the reversion of LPS-induced changes in Kv and Kir currents, partially mediated by the ALX receptor.
- These findings highlight e-LXA4 as a potential therapeutic agent for inflammation resolution by targeting macrophage ion channel function.
