Complement C3a-induced IL-17 plays a critical role in an IgE-mediated late-phase asthmatic response and airway hyperresponsiveness via neutrophilic inflammation in mice

• Published in: The Journal of immunology (1950) 2012-06, Vol.188 (11), p.5694-5705
• Main Authors: Mizutani, Nobuaki, Goshima, Hirofumi, Nabe, Takeshi, Yoshino, Shin
• Format: Article
• Language: English
• Subjects: Animals; Antibodies, Monoclonal - physiology; Asthma - immunology; Asthma - metabolism; Asthma - pathology; Bronchial Hyperreactivity - immunology; Bronchial Hyperreactivity - pathology; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - metabolism; CD4-Positive T-Lymphocytes - pathology; Complement C3a - antagonists & inhibitors; Complement C3a - immunology; Complement C3a - physiology; Immunoglobulin E - physiology; Inflammation Mediators - antagonists & inhibitors; Inflammation Mediators - immunology; Inflammation Mediators - physiology; Interleukin-17 - biosynthesis; Interleukin-17 - immunology; Interleukin-17 - physiology; Male; Mice; Mice, Inbred BALB C; Neutrophils - immunology; Neutrophils - pathology; Receptors, Complement - antagonists & inhibitors; Time Factors
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1103176

Allergen-specific IgE plays an essential role in the pathogenesis of allergic asthma. Although there has been increasing evidence suggesting the involvement of IL-17 in the disease, the relationship between IL-17 and IgE-mediated asthmatic responses has not yet been defined. In this study, we attempted to elucidate the contribution of IL-17 to an IgE-mediated late-phase asthmatic response and airway hyperresponsiveness (AHR). BALB/c mice passively sensitized with an OVA-specific IgE mAb were challenged with OVA intratracheally four times. The fourth challenge caused a late-phase increase in airway resistance associated with elevated levels of IL-17(+)CD4(+) cells in the lungs. Multiple treatments with a C3a receptor antagonist or anti-C3a mAb during the challenges inhibited the increase in IL-17(+)CD4(+) cells. Meanwhile, a single treatment with the antagonist or the mAb at the fourth challenge suppressed the late-phase increase in airway resistance, AHR, and infiltration by neutrophils in bronchoalveolar lavage fluid. Because IL-17 production in the lungs was significantly repressed by both treatments, the effect of an anti-IL-17 mAb was examined. The late-phase increase in airway resistance, AHR, and infiltration by neutrophils in bronchoalveolar lavage fluid was inhibited. Furthermore, an anti-Gr-1 mAb had a similar effect. Collectively, we found that IgE mediated the increase of IL-17(+)CD4(+) cells in the lungs caused by repeated Ag challenges via C3a. The mechanisms leading to the IgE-mediated late-phase asthmatic response and AHR are closely associated with neutrophilic inflammation through the production of IL-17 induced by C3a.