| Allergic asthma, a chronic airway inflammation, is characterized by recurring symptoms, reversible airflow obstruction, and bronchospasm Asthmatic pathological alterationsaretypically characterized as bronchial hyperresponsiveness (AHR), mucus hypersecretion and pulmonary eosinophil infiltration. Asthma is mediated by various cells including airway epithelia, dentritic cells, mast cells, eosnophils and lymphocytes. Both genetic factors and environmental factors, such as allergens, respiratory viral infections also contribute to the development of asthma. So far, there is no drug to effectively cure this disease. As a result, it is necessary to study the process and the pathogenesis of asthma. Reversible phosphorylation is a common posttranslational modification of proteins and reversible enzymatic reaction by kinase and phosphatase contributes to cell signal transduction. Despite lacking of catalytic domain, many studies have suggested that adaptor proteins play vital roles in signal transduction of phosphorylation by interaction with kinase and phosphatase. GAB (Grb2-associated binder) adaptor/scaffolding protein family is found from worms to mammals. Gabl and Gab2, containing PH (pleckstrin homologue) domain, tyrosine containing motifs and proline-rich sequences, are expressed widely in mammals. GABs have no enzymatic activity but provide docking sites for many enzymes (including phosphatases and kinases) and signal proteins, contributing to the triggering and amplification of specific pathway and mediating lots of physical processes, such as proliferation, apoptosis, migration and polarization. Recently, Gabl has been reported to be a new susceptibility gene of asthma. And we observed an elevated level of Gabl in PBMCs of asthmatic mice, while Gab2express has no significant change. At the same time, we found an elevated level of Gab2in airway epithelia of asthmatic mice. The same expression trend is also demonstrated in PBMCs of acute exacerbation in asthmatic patients. All these propose potential and different roles of Gabl and Gab2in asthma. As a result, we generated Gabl conditional KO mice in myeloid cells (LysmCre-Gabl flox/flox) and Gab2-/-mice to explore the role of these two proteins in asthma.In our study, we found that knockdown of Gab2in human airway epithelial cells in vitro decreases IL-13induced expression of mucin genes. Further analysis of lungs in the OVA-induced allergic model suggested that GCH and mucus production were remarkably reduced in Gab2-/-mice. Previous studies have demonstrated that PI3K/AKT and TYK2/STAT6pathways are both involved in regulating mucus secretion. Mechanistically, Gab2acts to positively regulate mucin gene expression through a TYK2/STAT6-dependent pathway by decreasing SOCS3-mediated degradation of TYK2.Meantime, in vivo study showed that loss of Gabl in mDCs, rather than in macrophages abolishes OVA-induced asthma, including reduced Th2-inflammatory cytokines (IL-4, IL-5and IL-13), less eosnophil and other lymphocyte infiltration and decreased mucus secretion. Further research found that loss of Gab1impairs CCL19-mediated DC migration and blocks the trafficking of DCs to lymph nodes while has little influence on the maturation, antigen uptake and antigen presentation of DCs. As homologus protein, adaptor protein Gabl and Gab2play different roles in allergic asthma. Gabl regulates allergic asthma by mediating DC-migration, while Gab2is involved in asthma by positively regulating GCH and mucus secretion of airway epithelium. This research helps us to better understand the pathogenesis of asthma and provides new potential targets for its diagnosis and treatment... |
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