EcN-Sj16-Exo ameliorates experimental asthma by inhibiting eosinophil extracellular trap formation via N-WASP...

Eosinophilic inflammation is a feature of allergic asthma, with eosinophil depletion shown to alleviate symptoms. Elevated levels of eosinophil extracellular traps (EETs) in bronchoalveolar lavage fluid (BALF) correlate with asthma severity. Sj16 is a protein from Schistosoma japonicum with known immunoregulatory properties. Exosomes, with their protective phospholipid bilayer, serve as efficient drug carriers.

We extracted exosomes secreted by Escherichia coli Nissle 1917 engineered to express Sj16 (EcN-Sj16-Exo), and sought to investigate the role of EcN-Sj16-Exo in asthma. In an ovalbumin-induced experimental asthma model in mice, EET levels were elevated. The experimental asthma model was treated with EcN-Sj16-Exo. EET formation was assessed using immunofluorescence and scanning electron microscopy. Lung function, airway remodelling and inflammation were evaluated. Wiskott-Aldrich syndrome-like (WASL) knockout mice and recombinant adeno-associated virus (rAAV)-expressing neural Wiskott-Aldrich syndrome protein (N-WASP) were used to investigate the potential mechanisms of EcN-Sj16-Exo.

EET formation is increased in sputum and BALF from patients with asthma. We demonstrate that Sj16 inhibits EET formation in vitro and localises primarily in exosomes when secreted by EcN-Sj16. In the experimental asthma model, EcN-Sj16-Exo significantly reduced EET formation. Moreover, EcN-Sj16-Exo significantly attenuated airway hyperreactivity and airway remodelling, as evidenced by reduced lung resistance, improved dynamic compliance and diminished inflammatory cell infiltration, fibrosis and mucus hypersecretion. Furthermore, EcN-Sj16-Exo decreased eosinophil and neutrophil counts, IgE levels and type 2 cytokine levels in BALF while increasing T-regulatory cells in the spleen. Mechanistically, EcN-Sj16-Exo inhibited EET formation by upregulating N-WASP. WASL-knockout mice and AAV6-WASL-mediated N-WASP expression confirmed that EcN-Sj16-Exo alleviates experimental asthma by upregulating N-WASP to inhibit EET formation.

Our findings suggest that EcN-Sj16-Exo represents a promising therapeutic approach in asthma, highlighting the potential of targeting EETs and N-WASP in asthma therapy.