Interleukin-33 modulates NET formation via an autophagy-dependent manner to promote neutrophilic inflammation in cigarette smoke-exposure asthma

Abstract

Cigarette smoke (CS) contributes to IL­33 release and neutrophil inflammation in asthma. Neutrophil extracellular traps (NETs) are essential for neutrophil functions. However, the effect of IL­33 on neutrophils in cigarette smoke­exposure asthma remains unclear. We found that CS exposure led to lower lung function and a neutrophil­related phenotype in asthma, characterized by elevated neutrophil and Th17 cell counts. Granulocytic airway inflammation was ablated by sST2, which blocked excessive IL­33 release. Transcriptome analysis of mouse lungs revealed that IL­33 enhanced NET formation in HDM/CS­treated mice, which was further confirmed in our experimental asthma model and in asthma patients. NETs were associated with poor lung function and airway inflammation and directly facilitated monocyte­derived dendritic cell activation, further inducing Th2/Th17 polarization. Furthermore, we demonstrated a feedforward loop between NETs and neutrophil autophagy, both of which are dependent on reactive oxygen species (ROS) production and the mTOR-HIF-1α signaling pathway. Notably, IL­33 knockout suppressed autophagy and NETs, whereas the autophagy agonist rapamycin reversed the inhibition of NETs by sST2 in a mTOR­dependent manner. Our findings revealed that the IL­33/ST2 signaling pathway interacts with the neutrophil ­autophagy­mTOR-HIF-1α -NET pathway, ultimately aggravating Th2/Th17-related inflammation. These insights could lead to potential therapeutic targets for mitigating exacerbations in asthmatic patients who are exposed to CS.