Fungal contamination is omnipresent, and inhalation of fungi-contaminated organic dust leads to hypersensitivity pneumonitis (HP), in which neutrophils played a pivotal role. Existing studies have suggested that cell homeostasis is crucial for the pathogenesis of the inflammatory disease. Although HMGB1 has been shown to contribute to suppressing HP, there is a lack of studies on its mechanisms, especially the regulation of neutrophil homeostasis. This study aims to investigate how HMGB1 regulates neutrophil function by affecting neutrophil homeostasis, and then affects lung inflammation induced by β-glucan, the exposure marker of fungi. Our results showed that deficient HMGB1 led to neutrophil death by disrupting the balance between autophagy and pyroptosis after β-glucan treatment. And HMGB1 deficiency exacerbated the β-glucan-induced lung inflammation and neutrophil dysfunction both in vivo and in vitro. Furthermore, HMGB1 contributed to remodeling neutrophil function by restricting autophagy and aggravating pyroptosis β-glucan exposure. Our funding suggested that HMGB1 deficiency could break the balance between autophagy and pyroptosis towards pyroptosis to cause neutrophil dysfunction during the exacerbated inflammatory response, which provides insights into the pathogenesis of HP and the potential biological targets for its treatment.

Data Availability

The datasets used during the current study are available from the corresponding author on reasonable request