?d+ 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. These Siglec-F+ neutrophils exhibited enhanced phagocytic activity, increased extracellular trap formation, and elevated production of pro-inflammatory cytokines, alongside reduced IL-10 levels, compared to conventional neutrophils. During the early phase of acute inflammation following PPE instillation, IL-17A levels in the lung increased, primarily driven by ?d+ 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, 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 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. Overall design: RNA-seq profiling of neutrophils derived from the bone marrow of C57BL/6J wild-type mice after 6 hours of stimulation with Medium or G-CSF.