Differential therapeutic activity of a cargo-free nanoparticle in eosinophilic and neutrophilic asthma mouse models

Abstract

Asthma is a complex, heterogeneous chronic airway inflammatory disorder, which can be simply categorized into eosinophilic and neutrophilic asthma. Although most patients with eosinophilic asthma can be well managed by glucocorticoid therapy, the patients with neutrophilic asthma have poor responses to corticosteroids, and there are no effective clinical treatments for neutrophilic asthma. Studies have shown that M1 macrophages are associated with the pathophysiology of neutrophilic asthma. We previously developed a novel cargo-free anti-inflammatory nanoparticle (P12), which can promote macrophage polarization from M1 to the M2 phenotype. Herein, we aim to explore the therapeutic activities of P12 in eosinophilic asthma and neutrophilic asthma and the mechanisms of action behind. Using the mouse models of eosinophilic and neutrophilic asthma, we found that the intratracheally administered P12 reduced the airway resistance in both models. However, P12 had higher therapeutic effects in neutrophilic asthma than in eosinophilic asthma, particularly on the pathological score, the serum IgE level, the BAL differential cell count and the proinflammatory cytokine IL-17A and IL-6 levels. Mechanistically, P12 facilitated M2 macrophage polarization by inhibiting transcription factors NF-κB and STAT1 activation and up-regulating STAT3 signaling in vitro; in the asthma models, P12 promoted M2 polarization of both alveolar and interstitial macrophages, and reduced the downstream Th17/Treg ratio in mice with neutrophilic asthma. Finally, P12 showed a good biosafety profile in healthy mice, facilitating the clinical translation of P12. This study provides a new strategy and lung macrophage targeted nanotherapeutics for the treatment of neutrophilic asthma.