Epithelial Interleukin-25 Contributes to the Nasal Polypogenesis in Chronic Rhinosinusitis

Chronic rhinosinusitis (CRS) with nasal polyps (NP) is associated with Th2 cytokine polarization. Interleukin (IL)-25 was recently reported to induce Th2-type immune responses and to contribute to several allergic diseases including atopic dermatitis and asthma. However, the role of IL-25 and its mechanism in nasal polyposis remain unclear. We investigated IL-25 expression and its cellular origins in NPs of human subjects by immunohistochemistry, qRT-PCR, and ELISA of NP tissues. Correlations between IL-25 and other inflammatory markers in NP tissues were also explored. To confirm the function of IL-25, anti-IL-25 neutralizing antibody was administered in the ovalbumin- and staphylococcal enterotoxin B (SEB)-induced murine NP model. IL-25 expression was upregulated in NP mucosa from patients with CRSwNP compared with the uncinate process tissue from control patients and those with CRSsNP. Overexpression of epithelial IL-25 was confirmed by immunohistochemistry, and double immunohistochemistry staining showed that tryptase positive cells were one of the main source of IL-25 among immune cells. Furthermore, IL-17RB was also increased in immune cells of nasal polyps, compared with control. In NPs, IL-25 mRNA expression positively correlated with the expression of several inflammatory markers, including T-bet, RORC, GATA3, ECP, TGF-b1, and TGF-b2. IL-25 was more abundant in the murine NP tissues than controls. Anti-IL-25 treatment reduced polyp number, mucosal edema, collagen deposition, and inflammatory cell inflitrations. This treatment also inhibited the expression of local inflammatory cytokines, such as IL-4 and IFN-g. Our findings suggests IL-25 in sinonasal mucosa play a crucial role in the pathogenesis of CRSwNP and could be a novel therapeutic target.