Endoplasmic reticulum (ER) stress results in the activation of the unfolded protein response (UPR), a process that is involved in the pathogenesis of many inflammatory diseases. However, the role of ER stress in chronic rhinosinusitis with nasal polyps (CRSwNP) has yet to be elucidated. In this study, we found that the protein expression levels of a range of ER stress regulators, including p-PERK, ATF4, ATF6 and XBP1s, were significantly increased in CRSwNP compared to controls. Importantly, the expression of ATF4 and XBP1s was positively correlated with heightened inflammation in CRSwNP. In human nasal epithelial cells, the ER stress inducer tunicamycin (TM) could potentiate Toll-like receptors (TLRs) induced proinflammatory cytokines production. Furthermore, we found that the silencing of XBP1, but not ATF4 or ATF6, abrogated the proinflammatory effect of TM. Mechanistically, ER stress did not affect the NF-κB, MAPK or IRF3 signaling pathways. However, the ER stress regulator XBP1s was able to bind directly to the promoter region of inflammatory genes to modulate gene transcription. Besides, the commensal bacteria Staphylococcus aureus and several inflammatory factors, such as IL4, IL13, IL17 and IFNγ, could induce ER stress in epithelial cells. Collectively, ER stress plays a crucial role in facilitating TLR-induced inflammation. Targeting XBP1 can inhibit the inflammatory response, thus offering a potential approach to treat CRSwNP.

内质网（ER）应力导致未折叠蛋白应答（UPR）的激活，该过程涉及许多炎性疾病的发病机理。然而，ER应激在慢性鼻窦炎伴鼻息肉（CRSwNP）中的作用尚待阐明。在这项研究中，我们发现与对照相比，CRSwNP中一系列ER应激调节剂（包括p-PERK，ATF4，ATF6和XBP1s）的蛋白表达水平显着增加。重要的是，ATF4和XBP1s的表达与CRSwNP中炎症加剧呈正相关。在人的鼻上皮细胞中，ER应激诱导剂衣霉素（TM）可以增强Toll样受体（TLR）诱导的促炎细胞因子的产生。此外，我们发现XBP1沉默，而不是ATF4或ATF6，消除了TM的促炎作用。从机理上讲，内质网应激并不影响NF-κB，MAPK或IRF3信号通路。然而，内质网应激调节剂XBP1s能够直接结合到炎症基因的启动子区域来调节基因转录。此外，共生细菌金黄色葡萄球菌和几种炎性因子，例如IL4，IL13，IL17和IFNγ，可以诱导上皮细胞内质网应激。总体而言，内质网应激在促进TLR诱导的炎症中起着至关重要的作用。靶向XBP1可以抑制炎症反应，因此提供了治疗CRSwNP的潜在方法。