NINJ1 plays a vital role in the release of neutrophil extracellular traps in acute lung injury

Excessive neutrophil extracellular traps (NETs) formation is a significant contributor to acute lung injury (ALI), making its inhibition a novel therapeutic avenue to improve outcomes. In this study, we revealed that a novel pore-forming protein ninjurin-1 (NINJ1) was predominantly highly expressed in pro-inflammatory neutrophil subpopulations during ALI, using public single-cell RNA sequencing and hotspot analysis. Furthermore, we demonstrated that the NINJ1 oligomerization was essential for the NETs release of neutrophils from both acute respiratory distress syndrome (ARDS) patients and ALI mice. Genetic ablation of Ninj1 in neutrophils abolished NETs release, thereby attenuating pulmonary dysfunction and reducing ALI-related lethality. Mechanistically, we found that N-glycosylation of NINJ1 at the 60 site was the major contributor to its oligomerization and NETs release. In summary, our findings reveal a novel pore-forming protein-mediated mechanism for NETs release and highlight NINJ1 as a potential therapeutic target for the treatment of ALI/ARDS.