γδ(+) T-cell-derived IL-17A stimulates airway epithelial/stromal cells to secrete G-CSF, promoting lung-specific pathogenic Siglec-F(+) neutrophil development in PPE-induced emphysema.

Neutrophils play a pivotal role in the progression of IL-17-mediated airway inflammation, but the mechanisms underlying their pathological differentiation remain poorly understood. In this study, we identified a distinct population of lung-specific pathogenic Siglec-F(+) neutrophils in a porcine pancreatic elastase (PPE)-induced mouse model of emphysema. Compared with conventional neutrophils, these Siglec-F(+) neutrophils exhibited increased phagocytic activity, increased extracellular trap formation, increased production of proinflammatory cytokines, and reduced IL-10 levels. During the early phase of acute inflammation following PPE instillation, IL-17A levels in the lungs increase, which is driven primarily by γδ(+) T cells. IL-17A stimulated lung epithelial/stromal cells to secrete granulocyte colony-stimulating factor (G-CSF), which promoted the differentiation of Siglec-F(+) neutrophils via the JAK2/STAT3 pathway and the PI3K-independent mTOR and p38 MAPK signaling pathways. Neutralizing G-CSF or inhibiting JAK2/STAT3, mTOR or p38 MAPK signaling significantly suppressed Siglec-F(+) neutrophil development, resulting in the alleviation of emphysematous symptoms. Our findings underscore the crucial role of Siglec-F(+) neutrophils in the pathogenesis of PPE-induced emphysema and suggest that targeting the IL-17A/G-CSF axis or G-CSF receptor downstream signaling pathways may represent a promising therapeutic strategy for treating emphysema.