Kv1.3 modulates macrophage M2 polarization via the STAT3 pathway: A novel mechanism and therapeutic target for...

Severe steroid-resistant asthma (SSRA) is characterized by persistent neutrophilic airway inflammation and limited glucocorticoid efficacy. Dysregulated macrophage polarization toward the pro-inflammatory M1 phenotype contributes to SSRA pathogenesis. The voltage-gated potassium channel Kv1.3 regulates immune cell activation, but its role in asthma-related macrophage polarization remains unclear.

We analyzed KCNA3 (Kv1.3-encoding gene) expression in alveolar macrophages from asthma patients (GSE2125 dataset). An OVA/LPS-induced SSRA mouse model was established and treated with the Kv1.3 inhibitor Margatoxin (MgTX), clarithromycin (CLA), or dexamethasone (DEX). Airway hyperresponsiveness (AHR) and lung pathology were evaluated. Macrophage phenotypes and STAT signaling were analyzed by flow cytometry, immunofluorescence, and Western blotting. Bone marrow-derived macrophages (BMDMs) were polarized in vitro with or without MgTX.

KCNA3 expression was significantly elevated in alveolar macrophages from asthma patients. In SSRA mice, MgTX and CLA outperformed DEX in reducing AHR, inflammation, and collagen deposition. Kv1.3 inhibition upregulated M2 markers (Arg-1, FIZZ1) and downregulated the M1 marker iNOS, and was associated with enhanced STAT3 phosphorylation (p-STAT3/STAT3 ratio increased ∼2.5-fold). In vitro, MgTX promoted BMDM M2 polarization through selective STAT3 activation without affecting STAT6.

Kv1.3 negatively correlates with STAT3 pathway activity, suggesting a potential inhibitory role in macrophage M2 polarization, which may contribute to sustained inflammation in SSRA. Pharmacological Kv1.3 inhibition is associated with restored macrophage balance and STAT3 activation, highlighting its potential as a novel therapeutic target for steroid-resistant asthma.