Neutrophils in nasal polyps exhibit transcriptional adaptation and proinflammatory roles that depend on local polyp milieu.

Abstract

Chronic rhinosinusitis with nasal polyps (CRSwNP) is an inflammatory upper airway disease, divided into eosinophilic CRSwNP (eCRSwNP) and noneosinophilic CRSwNP (neCRSwNP) according to eosinophilic levels. Neutrophils are major effector cells in CRSwNP, but their roles in different inflammatory environments remain largely unclear. We performed an integrated transcriptome analysis of polyp-infiltrating neutrophils from patients with CRSwNP, using healthy donor blood as a control. Additional experiments, including flow cytometry and in vitro epithelial cell and fibroblast culture, were performed to evaluate the phenotypic feature and functional role of neutrophils in CRSwNP. Single-cell RNA-sequencing analysis demonstrated that neutrophils could be classified into 5 functional subsets, with GBP5+ neutrophils occurring mainly in neCRSwNP and a high proportion of CXCL8+ neutrophils in both subendotypes. GBP5+ neutrophils exhibited significant IFN-I pathway activity in neCRSwNP. CXCL8+ neutrophils displayed increased neutrophil activation scores and mainly secreted oncostatin M (OSM), which facilitates communication with other cells. In vitro experiments showed that OSM enhanced IL-13- or IL-17-mediated immune responses in nasal epithelial cells and fibroblasts. Our findings indicate that neutrophils display transcriptional plasticity and activation when exposed to polyp tissue, contributing to CRSwNP pathogenesis by releasing OSM, which interacts with epithelial cells and fibroblasts depending on the inflammatory environment.