Adipocyte-derived exosomal miR-27a-3p promotes macrophage M1 polarization via HACE1/RAC1/STAT3 axis to exacerbate the progression of childhood asthma.

Adipocyte-derived exosomal miRNAs are emerging as potential therapeutic agents for various diseases. However, the molecular connections between these miRNAs and macrophage polarization in asthma remain unclear. Exosomes were isolated from the plasma of children with obesity, asthma, or obesity-associated asthma. A co-culture system of macrophages and adipocytes was used to assess exosome-mediated macrophage polarization. The interactions among miR-27a-3p, HACE1, and the RAC1/STAT3 pathway were analyzed using bioinformatic predictions, RT-qPCR, dual-luciferase reporter assays, co-immunoprecipitation, and Western blot. The functional role of exosomal miR-27a-3p was further examined in a murine model of obesity-related asthma. Elevated expression of miR-27a-3p in exosomes and alveolar macrophages was observed in patients with obesity and asthma. In vitro co-culture of adipocytes and macrophages enhanced the expression of M1 macrophage markers, including iNOS, IL-6, and TNF-α, an effect that was reversed by the exosome generation inhibitor GW4869. Moreover, exosomal miR-27a-3p derived from adipocytes was capable of being internalized by macrophages, promoting M1 polarization. Mechanistically, miR-27a-3p directly targets HACE1 mRNA, inhibiting HACE1 expression. This inhibition reduces HACE1-mediated ubiquitin-dependent degradation of RAC1, thereby stabilizing the RAC1 protein and enhancing the phosphorylated activation of STAT3, ultimately driving M1 polarization of macrophages. In vivo, inhibition of adipocyte-derived exosomal miR-27a-3p ameliorated airway resistance and inflammation and suppressed macrophage M1 polarization in asthmatic mice. These findings indicate that adipocyte-derived exosomal miR-27a-3p exacerbates asthma progression by downregulating HACE1 expression and activating the RAC1/STAT3 signaling pathway, which induces macrophage M1 polarization. This study provides novel insights and identifies a promising molecular candidate for asthma therapy.