2. Academic Validation
  3. 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

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

  • Cell Mol Immunol. 2025 Jul;22(7):791-805. doi: 10.1038/s41423-025-01301-x.
JungHyub Hong 1 2,  Myeong-Ho Kang 1 2,  Jinjoo Lee 1 2,  Min-Suk Cha 1 2,  Yoe-Sik Bae 1 2 3,  Hye Young Kim 2 4 5,  Yong Taik Lim 2 6,  Yong-Soo Bae 7 8
Affiliations

Affiliations

  • 1 Department of Biological Sciences, Sungkyunkwan University, Suwon, Republic of Korea.
  • 2 Center for Immune Research on Nonlymphoid Organs, Sungkyunkwan University, Suwon, Republic of Korea.
  • 3 Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul, Republic of Korea.
  • 4 Laboratory of Mucosal Immunology, Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea.
  • 5 Institute of Allergy and Clinical Immunology, Seoul National University Medical Research Center, Seoul, Republic of Korea.
  • 6 Department of Nano Engineering and School of Chemical Engineering, Sungkyunkwan University, Suwon, Republic of Korea.
  • 7 Department of Biological Sciences, Sungkyunkwan University, Suwon, Republic of Korea. ysbae04@skku.edu.
  • 8 Center for Immune Research on Nonlymphoid Organs, Sungkyunkwan University, Suwon, Republic of Korea. ysbae04@skku.edu.
PMID: 40461699 DOI: 10.1038/s41423-025-01301-x
Abstract

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.

Keywords

Emphysema; Epithelial/stromal cells; G-CSF; G-CSF receptor signaling; IL-17A; Porcine pancreatic elastase (PPE); Siglec-F+ neutrophils; γδ+ T cells.

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