Eosinophil-derived interferon-gamma drives transmembrane protein 119-induced new bone formation in chronic rhinosinusitis with nasal polyps

Abstract

Background: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a chronic inflammatory sinonasal disease characterized by eosinophilic infiltration and new bone formation. These changes indicate the severity and prognosis of CRSwNP and may be closely linked to each other. Methods: We performed RNA sequencing to screen specific osteogenic molecules and validated transmembrane protein 119 (TMEM119) expression by quantitative polymerase chain reaction (qPCR) and immunohistochemistry analyses. TMEM119 knockdown was performed to observe the downregulation of bone mineralization. We validated the bone-forming activity of interferon-gamma (IFN-gamma) and its signaling pathways in cultured primary sinus bone cells. Cellular sources of IEN-gamma were identified using immunohistochemistry and immunofluorescence analyses. Interleukin-4-eosinophil-IFN-gamma axis and the effect of dupilumab were investigated in Eol-1 cells. Results: We observed elevated IFN-gamma levels and eosinophils in the nasal fluid and predominantly eosinophil-derived IFN-gamma in the sinus mucosa of patients with CRSwNP. TMEM119 expression and bone-forming activities were increased in the osteitic and primary sinus bone cells of CRSwNP. IFN-gamma treatment enhanced bone mineralization and TMEM119 expression via signal transducer and activator of transcription 1 (STAT1) signaling. Moreover, TmEm119 knockdown inhibited sinus bone cell mineralization and dupilumab attenuated IFN-gamma secretion by IL4-stimulated Eol-1 cells. Conclusion: Eosinophil-derived IFN-gamma promotes the bone-forming activities of sinus bone cells via the STAT1-TMEM119 signaling pathway. Interleukin-4-eosinophil-IFN-gamma axis may be crucial for TMEM119-mediated new bone formation in CRSwNP.