IL-25 Promotes Th2 Immunity Responses In Asthmatic Mice Via Nuocytes Activation

BACKGROUND Asthma is a chronic inflammatory airway disease,which involve in a variety of inflammatory cells such as eosinophils (EOS), mast cells, T lymphocytes and various cellular components.Usually the structural changes in the airway epithelium are the pathological features. Three main pathological changes of bronchial asthma include:airway inflammation, airway remodeling and smooth muscle dysfunction. Chronic inflammation can cause release of some cytokines and cellular mediators,and these inflammatory cytokines and inflammatory mediators can cause airway inflammatory changes by a certain way. Asthma make bronchioles spasm and mucus secretion, causing airway narrowing and airway hyperresponsiveness. More current research revolves T h1/T h2 cytokine imbalance theory. CD4+Th2 cell activation and release interleukin-5 (IL-5) and interleukin-13 (IL-13) and other inflammatory cytokines, promote EOS recruitment to the airways, excessive mucus secretion, epithelial cell hypertrophy, prompting the B cell to convert to IgE secretory cells, resulting in increased serum IgE levels, causing airway hyperresponsiveness. Many studies have shown that interleukin-25 (IL-25) induce Th2 type cytokines production, participate in many aspects of airway inflammation including airway remodeling.So,IL-25 is closely related to asthma. The study also noted that the airway innate immune cells can also generate IL-5 and IL-13 and other Th2 cytokines, therefore speculated that type II cytokine pathways could activated by innate immune cells. Nuocytes are currently found as one of the type II inherent lymphocytes (type ? innate lymphoid cells, ILC2s), which play an important role in cellular immune response,the earliest found in the intestinal tract,and exist widely in bone marrow, peripheral blood, spleen. In recent years, we found that nuocytes promote Th2 type cytokines expression in the cellular immune response. A large number of nuocytes was also found in asthma animal models. The surface of nuocytes in asthma animal models also found the expression of IL-25 receptors. Thus,the interact of IL-25, nuocytes and Th2 cytokines become research focus about asthmatic pathogenesis, and may open a new direction for the treatment of asthma.PURPOSE To investigate the relationship between IL-25 and Th2 type cytokines expression in the airway inflammation of asthma animal models,and the effection of IL-25 and nuocytes in asthma through inducing asthma model in mice.METHODS In this study, the BALB/C mice were randomly divided into three groups, named for the asthma group, the anti-IL-25 group and the control group.OVA sensitization and challenge were used to induce the mouse model of asthma in the asthma groupand the anti-IL-25 group. In addition, anti-IL-25 group murine were instillated with anti-IL-25 antibody (0.5mg/each)through nasal.The murine asthma model was validated by histology. BALF was used to analyse leukocyte and eosinophil count and percentage.IL-25 expression was detected by ELISA, quantitative real-time PCR and western blotting in the lung tissue. Th2-cell producing cytokines (IL-5 and IL-13) in BALF were identified by ELISA. The nuocytes activation was identified by the levels of ICOS(clone C398.4A) and T1/ST2 (cloneDJ8) as nuocytes surface markers in bronchoalveolar lavage fluid (BALF) by flow cytometry.Result In the asthma group,the number of white blood cells and eosinophils increased in BALF.A large number of inflammatory cells infiltrated around bronchial mucosa and alveolar, mucus secreting cells increased, a lot of mucus secretions gathered in the bronchus.The mice sensitized and challenged with OVA showed a high expression of IL-25 in both the mRNA and protein levels in lungs. The expressions of ICOS and T1/ST2 in BALF were increased. A significant correlation between IL-25 mRNA, protein, and other Th2-cell producing cytokines (such as IL-5 and IL-13) moreover were identified. Furthermore, when the asthmatic mice were treated with anti-IL-25, both the inflammatory cells'infiltration and the inflammatory cytokines' secretion were significantly decreased. The present findings indicate that IL-25 might be involved in a series of asthmatic immune responses, playing an important role in the increase of nuocytes, and that its activation is necessary in maintaining Th2 central memory and sustaining asthmatic inflammation.CONCLUSION This study showed that IL-25 promoted the accumulation of ICOS and T1/ST2 on nuocytes, further induced the pro-inflammatory Th2 cells, and promoted Th2 cytokine responses in OVA-induced airway inflammation.Anti-IL-25 antibody can block this pathway, which is expected to become a new target for the treatment of asthma.