Interferon‐γ‐induced insufficient autophagy contributes to p62‐dependent apoptosis of epithelial cells in chronic rhinosinusitis with nasal polyps

Abstract Background Autophagy is a lysosomal degradation pathway that is essential for cell survival, differentiation, and homeostasis. This study aimed to investigate the contribution of autophagy to the pathogenesis of CRS with nasal polyps ( CRS w NP ). Methods The expression of autophagic proteins [microtubule‐associated protein 1 light chain 3B ( LC 3B)‐ II , autophagy‐related proteins (Atg), and Beclin 1], substrate proteins (p62 and ubiquitinated proteins), and apoptotic signaling molecules [cysteine‐aspartic protease‐3 and cysteine‐aspartic protease‐8, and poly‐ ADP ‐ribose polymerase] in the sinonasal mucosa and nasal epithelial cells ( NEC s) was detected by immunohistochemistry and Western blotting. Autophagic vacuoles were observed with transmission electron microscopy. BEAS ‐2B cells and NEC s were treated with rapamycin, bafilomycin A1, or various cytokines. In some experiments, cultured NEC s were transfected with small interfering RNA targeting p62 (sip62) or Atg5 (siAtg5). Cultured cells were analyzed with Western blotting and flow cytometry. Results Although autophagic protein expression and autophagic vacuole formation were increased in both eosinophilic and noneosinophilic CRS w NP , particularly in NEC s, there was also an up‐regulation of substrate proteins and apoptotic signaling molecules. IFN ‐γ, but not IL ‐4, IL ‐13, or IL ‐17A, simultaneously enhanced LC 3B‐ II and p62 levels as well as cell apoptosis in BEAS ‐2B cells and/or normal NEC s. Bafilomycin A1 up‐regulated the levels of LC 3B‐ II and p62 in polyp NEC s and IFN ‐γ‐treated normal NEC s. IFN ‐γ‐induced apoptosis of normal NEC s was exaggerated by bafilomycin A1 and siAtg5. Sip62 suppressed apoptosis of polyp NEC s and IFN ‐γ‐treated NEC s. IFN ‐γ protein levels were increased in both eosinophilic and noneosinophilic CRS w NP . Conclusions IFN ‐γ induces activated but insufficient autophagy and thus contributes to a degree to p62‐dependent apoptosis of NEC s in CRS w NP .