IL-25 as a novel therapeutic target in nasal polyps of patients with chronic rhinosinusitis

• Published in: Journal of allergy and clinical immunology Vol. 135; no. 6; pp. 1476 - 1485.e7
• Main Authors: Shin, Hyun-Woo, Kim, Dong-Kyu, Park, Min-Hyun, Eun, Kyoung Mi, Lee, Mingyu, So, Daeho, Kong, Il Gyu, Mo, Ji-Hun, Yang, Min-Suk, Jin, Hong Ryul, Park, Jong-Wan, Kim, Dae Woo
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.06.2015; Elsevier Limited
• Subjects: Adult; allergy; Allergy and Immunology; animal models; Animals; Antibodies, Monoclonal - pharmacology; Case-Control Studies; Cell Adhesion Molecules - genetics; Cell Adhesion Molecules - immunology; Chronic Disease; Disease; Disease Models, Animal; Endoscopy; Eosinophil Cationic Protein - genetics; Eosinophil Cationic Protein - immunology; Eosinophils - drug effects; Eosinophils - immunology; Eosinophils - pathology; Family medical history; Female; GATA3 Transcription Factor - genetics; GATA3 Transcription Factor - immunology; Gene Expression - drug effects; Gene Expression - immunology; Humans; IL-25; Immunoglobulins; Interleukin-17 - antagonists & inhibitors; Interleukin-17 - genetics; Interleukin-17 - immunology; Laboratories; Male; Mice; Middle Aged; Nasal polyp; Nasal Polyps - complications; Nasal Polyps - drug therapy; Nasal Polyps - genetics; Nasal Polyps - immunology; Neutrophils - drug effects; Neutrophils - immunology; Neutrophils - pathology; Nuclear Receptor Subfamily 1, Group F, Member 3 - genetics; Nuclear Receptor Subfamily 1, Group F, Member 3 - immunology; Proteins; Pulmonary fibrosis; Quality of life; Receptors, Interleukin-17 - genetics; Receptors, Interleukin-17 - immunology; Rhinitis - complications; Rhinitis - drug therapy; Rhinitis - genetics; Rhinitis - immunology; Rodents; sinusitis; Sinusitis - complications; Sinusitis - drug therapy; Sinusitis - genetics; Sinusitis - immunology; Surgery; T-Box Domain Proteins - genetics; T-Box Domain Proteins - immunology; Transforming Growth Factor beta1 - genetics; Transforming Growth Factor beta1 - immunology; Transforming Growth Factor beta2 - genetics; Transforming Growth Factor beta2 - immunology; animal models; NP; Nasal polyp; ICAM; CRS; IHC; RORC; allergy; IL-25; CRSwNP; T-bet; CRSsNP; CT; SEB; VCAM; ECP; IL-17R; sinusitis; OVA; UP; hpf; Immunohistochemistry; Chronic rhinosinusitis; IL-17 receptor; Computed tomography; Ovalbumin; RAR-related orphan receptor C; Vascular cell adhesion molecule; High-power field; Intercellular adhesion molecule; Chronic rhinosinusitis without nasal polyps; Chronic rhinosinusitis with nasal polyps; Staphylococcal enterotoxin B; T-box transcription factor; Eosinophil cationic protein; Uncinate process
• ISSN: 0091-6749; 1097-6825; 1097-6825
• DOI: 10.1016/j.jaci.2015.01.003

Chronic rhinosinusitis (CRS) with nasal polyps (NPs) in Western populations is associated with TH2 cytokine polarization. IL-25, an IL-17 family cytokine, was recently reported to induce TH2-type immune responses and to contribute to several allergic diseases, such as atopic dermatitis and asthma. However, the role of IL-25 in Asian patients with nasal polyposis remains unclear. We sought to determine the role of IL-25 in Asian patients with nasal polyposis and CRS. We investigated IL-25 expression and its cellular origins in NPs of human subjects using immunohistochemistry (IHC), quantitative RT-PCR, and ELISA of NP tissues. Correlations between IL-25 expression and expression of other inflammatory markers in NP tissues were also explored. Anti–IL-25 neutralizing antibody was administered in an ovalbumin- and staphylococcal enterotoxin B–induced murine NP model to confirm the function of IL-25 during nasal polypogenesis. IL-25 expression was upregulated in NP mucosa from patients with CRS with NPs compared with uncinate process tissue from control subjects and those with CRS without NPs. Overexpression of epithelial IL-25 was confirmed by using IHC, and double IHC staining showed that tryptase-positive cells were one of the main sources of IL-25 among immune cells. Furthermore, IL-17 receptor B levels were also increased in immune cells of patients with NPs compared with those in control subjects. In NPs IL-25 mRNA expression positively correlated with the expression of several inflammatory markers, including T-box transcription factor, RAR-related orphan receptor C, GATA3, eosinophil cationic protein, TGF-β1, and TGF-β2. IL-25 was more abundant in the murine NP model compared with control mice, and similar correlations between IL-25 and inflammatory markers were observed in murine models. Anti–IL-25 treatment reduced the number of polyps, mucosal edema thickness, collagen deposition, and infiltration of inflammatory cells, such as eosinophils and neutrophils. This treatment also inhibited expression of local inflammatory cytokines, such as IL-4 and IFN-γ. Furthermore, expression of CCL11, CXCL2, intercellular adhesion molecule 1, and vascular cell adhesion molecule 1 in the nasal mucosa was suppressed in the anti–IL-25–treated group. Our results suggest that IL-25 secreted from the sinonasal epithelia and infiltrating mast cells plays a crucial role in the pathogenesis of CRS with NPs in Asian patients. In addition, our results suggest the novel possibility of treating nasal polyposis with anti–IL-25 therapy.