| Allergic asthma, a form of chronic small airway inflammatory disease, belongs to type I hypersensitivity. The major pathological features include airway hyper-responsiveness, eosinophils, goblet cell metaplasia and excessive mucus production. Currently, a curative and safe therapy for asthma is lacking. Therefore, analyzing the pathogenesis of asthma as well as its regulatory process is great significance for the diagnosis and treatment of asthma.Dendritic cells (DCs), the most powerful antigen presenting cells, are considered as a bridge connecting innate immunity and adaptive immunity. When external antigens invade the airway, DCs will recognize andphagocytose them. During the processing, DCs also migrate towards lymph node nearby and mature. After entering into the lymph node, DCs stimulate native T cells to differentiate into Th2 cells, which further activate the B cells to produce amounts of IgE antibody to adsorb to the surface of mast cells. If the same antigens invade into organism again, they will be bind to IgE antibody and induce the activation of mast cells, which may produce amounts of active medium and induce airway spasm and inflammation.Protein phosphatase and kinase-mediated reversible phosphorylation is the most widespread and most common regulation manner in cell signaling pathway. The most common regulation manner of cell signaling pathway is reversible phosphorylation mediated by protein phosphatase and kinase. Shp2 is encoded by PTPN11 gene, which is a widely expressed non-receptor tyrosine phosphatase, and it participates many critical pathophysiological processes such as inflammatory response, tumorigenesis, immune regulation and so on. However, there is no research focused on the regulation mechanism of the key initial process of asthma.Previous research has shown that Shp2 is involved in the regulation of lung epithelial damage and lung inflammation, suggesting the critical roles of Shp2 in regulating lung damage. Current research about the effect of Shp2 on asthma are mainly focused on the late phase inflammation, including maintaining the survival of IL-5 induced eosinophils, and regulating the production of TGF-β from airway epithelial cells for affecting the airway remodeling. Recent research also discovered that Shp2 mediated DCs against Candida albicans infection process through type C lectin receptor pathway. This suggests the important role of Shp2 in immune response mediated by DCs.In this research, we firstly constructed DCs specific Shp2 knock-out mice (Cdllc-CreShp2 Flox/FIox) and then found that there is no significant difference in lung tissue structure, white blood cell count between control and knock-out mice without external pressures. And Shp2 deletion in DCs can alleviate HDM/OVA-induced allergic asthma. The phagocytosis, maturation, migration and antigen presentation of DCs play critical roles in the progression of asthma. Therefore we performed the analysis of these functions separately. We coincubated Alexa-Flour 647-coupled OVA and bone marrow-derived DCs (BMDC) to detect the phagocytic capacity of DCs. The result showed that Shp2 deletion did not affect the phagocytosis of DCs. Next, the expression of DCs surface markers Cdllc and its maturation associated costimulatory molecules CD80 and CD86 were assayed by flow cytometry. We found that Shp2 deletion had no impact on the expression of CD80 and CD86. Then we applied Transwell assay to measure the migration of DCs, and it was found that Shp2 deletion could significantly suppress the migration of DCs. Finally, we discovered that Shp2 knock-out in DCs could affect the rearrangement of cytoskeleton.Based on these results above, we found that Shp2 has impact on the pathological progression of asthma mainly through regulating the DCs migration. This study may contribute to the better understanding of the pathogenesis of allergenic asthma, and may provide a new therapeutic target for diagnosis and treatment of this disease. |
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