Takeshi Tsuda1, Masayuki Nishide2, Yohei Maeda3, Yoshitomo Hayama4, Shohei Koyama5, Satoshi Nojima6, Hyota Takamatsu5, Daisuke Okuzaki7, Takayoshi Morita5, Takeshi Nakatani5, Yasuhiro Kato5, Yoshimitsu Nakanishi5, Yu Futami5, Yasuhiko Suga5, Yujiro Naito5, Hachiro Konaka5, Shingo Satoh5, Maiko Naito5, Mayuko Izumi5, Sho Obata1, Ayaka Nakatani3, Takashi Shikina8, Kazuya Takeda9, Masaki Hayama3, Hidenori Inohara3, Atsushi Kumanogoh10. 1. Department of Otorhinolaryngology-Head and Neck Surgery, Osaka University Graduate School of Medicine, Suita City, Osaka, Japan; Department of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, Suita City, Osaka, Japan; Laboratory of Immunopathology, World Premier International Immunology Frontier Research Center, Suita City, Osaka, Japan. 2. Department of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, Suita City, Osaka, Japan; Laboratory of Immunopathology, World Premier International Immunology Frontier Research Center, Suita City, Osaka, Japan. Electronic address: nishide@imed3.med.osaka-u.ac.jp. 3. Department of Otorhinolaryngology-Head and Neck Surgery, Osaka University Graduate School of Medicine, Suita City, Osaka, Japan. 4. Department of Respiratory Medicine, Kinki Central Hospital, Itami City, Hyogo, Japan. 5. Department of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, Suita City, Osaka, Japan; Laboratory of Immunopathology, World Premier International Immunology Frontier Research Center, Suita City, Osaka, Japan. 6. Laboratory of Immunopathology, World Premier International Immunology Frontier Research Center, Suita City, Osaka, Japan; Department of Pathology, Osaka University Graduate School of Medicine, Suita City, Osaka, Japan. 7. Genome Information Research Center, Research Institute for Microbial Diseases, Osaka University, Suita City, Osaka, Japan. 8. Department of Otorhinolaryngology-Head and Neck Surgery, Osaka University Graduate School of Medicine, Suita City, Osaka, Japan; Department of Otolaryngology, Ikeda Municipal Hospital, Ikeda City, Osaka, Japan. 9. Department of Otolaryngology, Osaka City General Hospital, Osaka City, Osaka, Japan. 10. Department of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, Suita City, Osaka, Japan; Laboratory of Immunopathology, World Premier International Immunology Frontier Research Center, Suita City, Osaka, Japan; Institute for Open and Transdisciplinary Research Initiatives, Suita City, Osaka, Japan. Electronic address: kumanogo@imed3.med.osaka-u.ac.jp.
Abstract
BACKGROUND: Eosinophilic chronic rhinosinusitis (ECRS) is a subtype of chronic rhinosinusitis. Clinical markers for ECRS disease activity and treatment strategies have not been sufficiently established. Although semaphorins are originally identified as neuronal guidance factors, it is becoming clear that they play key roles in immune regulation and inflammatory diseases. OBJECTIVE: We sought to investigate the pathological functions and therapeutic potential of semaphorin 4D (SEMA4D) in ECRS. METHODS: Serum soluble SEMA4D levels in patients with paranasal sinus diseases were measured by ELISA. The expression of SEMA4D in blood cells and nasal polyp tissues was assessed by flow cytometry and immunohistochemistry, respectively. Generation of soluble SEMA4D was evaluated in matrix metalloproteinase-treated eosinophils. Endothelial cells were stimulated with recombinant SEMA4D, followed by eosinophil transendothelial migration assays. Allergic chronic rhinosinusitis was induced in mice using Aspergillus protease with ovalbumin. The efficacy of treatment with anti-SEMA4D antibody was evaluated histologically and by nasal lavage fluid analysis. RESULTS: Serum soluble SEMA4D levels were elevated in patients with ECRS and positively correlated with disease severity. Tissue-infiltrated eosinophils in nasal polyps from patients with ECRS stained strongly with anti-SEMA4D antibody. Cell surface expression of SEMA4D on eosinophils from patients with ECRS was reduced, which was due to matrix metalloproteinase-9-mediated cleavage of membrane SEMA4D. Soluble SEMA4D induced eosinophil transendothelial migration. Treatment with anti-SEMA4D antibody ameliorated eosinophilic infiltration in sinus tissues and nasal lavage fluid in the ECRS animal model. CONCLUSIONS: Eosinophil-derived SEMA4D aggravates ECRS. Levels of serum SEMA4D reflect disease severity, and anti-SEMA4D antibody has therapeutic potential as a treatment for ECRS.
BACKGROUND:Eosinophilic chronic rhinosinusitis (ECRS) is a subtype of chronic rhinosinusitis. Clinical markers for ECRS disease activity and treatment strategies have not been sufficiently established. Although semaphorins are originally identified as neuronal guidance factors, it is becoming clear that they play key roles in immune regulation and inflammatory diseases. OBJECTIVE: We sought to investigate the pathological functions and therapeutic potential of semaphorin 4D (SEMA4D) in ECRS. METHODS: Serum soluble SEMA4D levels in patients with paranasal sinus diseases were measured by ELISA. The expression of SEMA4D in blood cells and nasal polyp tissues was assessed by flow cytometry and immunohistochemistry, respectively. Generation of soluble SEMA4D was evaluated in matrix metalloproteinase-treated eosinophils. Endothelial cells were stimulated with recombinant SEMA4D, followed by eosinophil transendothelial migration assays. Allergic chronic rhinosinusitis was induced in mice using Aspergillus protease with ovalbumin. The efficacy of treatment with anti-SEMA4D antibody was evaluated histologically and by nasal lavage fluid analysis. RESULTS: Serum soluble SEMA4D levels were elevated in patients with ECRS and positively correlated with disease severity. Tissue-infiltrated eosinophils in nasal polyps from patients with ECRS stained strongly with anti-SEMA4D antibody. Cell surface expression of SEMA4D on eosinophils from patients with ECRS was reduced, which was due to matrix metalloproteinase-9-mediated cleavage of membrane SEMA4D. Soluble SEMA4D induced eosinophil transendothelial migration. Treatment with anti-SEMA4D antibody ameliorated eosinophilic infiltration in sinus tissues and nasal lavage fluid in the ECRS animal model. CONCLUSIONS: Eosinophil-derived SEMA4D aggravates ECRS. Levels of serum SEMA4D reflect disease severity, and anti-SEMA4D antibody has therapeutic potential as a treatment for ECRS.