Endoplasmic reticulum stress exacerbates inflammation in chronic rhinosinusitis with nasal polyps via the transcription factor XBP1.

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.