Eosinophil‐derived interferon‐γ 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‐γ (IFN‐γ) and its signaling pathways in cultured primary sinus bone cells. Cellular sources of IFN‐γ were identified using immunohistochemistry and immunofluorescence analyses. Interleukin‐4–eosinophil–IFN‐γ axis and the effect of dupilumab were investigated in Eol‐1 cells. Results We observed elevated IFN‐γ levels and eosinophils in the nasal fluid and predominantly eosinophil‐derived IFN‐γ 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‐γ 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‐γ secretion by IL4‐stimulated Eol‐1 cells. Conclusion Eosinophil‐derived IFN‐γ promotes the bone‐forming activities of sinus bone cells via the STAT1–TMEM119 signaling pathway. Interleukin‐4–eosinophil–IFN‐γ axis may be crucial for TMEM119‐mediated new bone formation in CRSwNP.

MicroRNA-145-5p Regulates the Epithelial-Mesenchymal Transition in Nasal Polyps by Targeting Smad3

“…Second, the pathways involved in the EMT include the nuclear factor kappa B, Wnt/β-catenin, and Akt pathways apart from the well-known TGF-β pathway [8,41,42]. Finally, substances such as the cytokines interferongamma and hypoxia-inducible factor-alpha were equally involved in the EMT [43,44]. miR-145-5p is expected to be a key target for the treatment of nasal polyps.…”