Ethyl ferulate attenuates allergic asthma by inhibiting macrophage M2 polarization via STAT6/IRF4 pathway

Allergic asthma (AA) is a chronic airway inflammatory disease characterized by persistent inflammation, airway hyperresponsiveness, and remodeling, for which current therapeutic options often have limitations or side effects. Macrophages play a critical role in AA pathogenesis, with M2 macrophages specifically promoting inflammation, tissue remodeling, and mucus secretion. Targeting M2 macrophage polarization offers a promising strategy to alleviate AA symptoms. Ethyl ferulate (EF), a natural compound found in traditional medicinal plants, has demonstrated various biological activities, but its specific effects and mechanisms in AA, particularly regarding macrophage modulation, have been largely unexplored.

Researchers utilized a house dust mite (HDM)-induced allergic asthma mouse model to investigate the therapeutic potential of Ethyl ferulate (EF). Mice were exposed to HDM to induce allergic asthma and subsequently treated with EF (specific dose and route not detailed in abstract). The study assessed EF's impact on airway inflammation, eosinophil infiltration, mucus secretion, and airway remodeling. To confirm the role of M2 polarization, adoptive transfer experiments were conducted. Mechanistic studies employed IL-4-stimulated RAW264.7 cells and bone marrow-derived macrophages (BMDMs) to analyze STAT6 phosphorylation and IRF4 pathway activity, using techniques like western blot and immunofluorescence to evaluate protein expression and localization.

Ethyl ferulate (EF) treatment significantly attenuated several key features of HDM-induced allergic asthma in mice. This included a marked reduction in airway inflammation, decreased eosinophil infiltration into the lungs, suppressed mucus secretion, and amelioration of airway remodeling. Furthermore, EF effectively suppressed the expression of canonical M2 macrophage markers, including CD206, Arg1, Ym1, and Fizz1, both in lung tissues from asthmatic mice and in IL-4-stimulated macrophages. Mechanistically, EF's action was traced to its ability to block STAT6 phosphorylation and its subsequent nuclear translocation. > This disruption effectively inhibited the entire STAT6/IRF4 signaling pathway, which is crucial for M2 macrophage polarization. These findings strongly indicate that EF exerts its therapeutic effects in allergic asthma by directly interfering with the pro-inflammatory M2 macrophage phenotype.