The Mechanism Of Tyrosine Phosphatase Shp2 Regulating Dendritic Cell Migration In Lung Injury

Dendritic cell(DC)migration induced by environmental allergens is a key step in allergic inflamation.Asthma is a common chronic airway inflammation disease.Airway remodeling,airway hyperresponsiveness,and reversible airflow restriction are important pathophysiological characteristics of asthma.The clinical manifestations of asthma include recurrent wheezing,chest tightness,cough and so on.According to the latest statistics from the World Health Organization,about 300 million people suffer from asthma.In addition,the incidence and mortality of asthma are increased in recent years,which has brought heavy economic burdens to the society and many families.At present,there is no effective means to cure asthma,so exploring the pathogenesis of asthma and its regulation process is important for the precise treatment of asthma.DCs are the most potent professional antigen presenting cells(APC)and DC migration to lymph nodes is crucial for initiation and progression of adaptive immune responses.Numerous studies have shown that DC plays a central role in the initiation of allergic asthma.It is the only APC currently known to activate initial T cell differentiation.Therefore,it is important to study the specific molecular mechanism that regulates the occurrence of asthma and significance for the diagnosis and treatment of asthma.Spatiotemporal DC migration is tightly regulated by rho family small guanosine triphosphatases(GTPases).Most Rho GTPases cycle is between an active GTP-bound conformation and an inactive GDP-bound conformation.This cycling is regulated by Guanine nucleotide exchange factors(GEFs)and GTPase-activating proteins(GAPs).GEFs catalyse the exchange of GDP for GTP,thereby activating the GTPase.DC migration is precisely regulated by sophisticated cellular signals.Analyzing key regulatory molecules in DCs will help understand the pathogenesis and pathological processes of allergic asthma.Reversible phosphorylation regulation mediated by protein kinases and phosphatases is the most extensive and universal regulation method in cell signaling.Shp2 is a member of the non-receptor tyrosine phosphatase family,which includes two SH2 domains and a PTP active domain.In the absence of upstream stimulation,Shp2 is kept in a low-activity state by interaction of the N-terminal SH2-domain with the protein-tyrosine phosphatase(PTP)domain.N-SH2 separates from PTP domain under various stimulation including chemokines and growth factors result in active Shp2 to dephosphorylation substrate.Previous articles reported that Shp2 can regulate allergen-induced eosinophil recruitment into lungs and airway hyperreactivity as well.Our laboratory found that Shp2 can participate in the regulation of lung inflammation and lung epithelial damage.However,the physiologic functions of Shp2 and in vivo mechanism of action in DCs are still undetermined.In our study,we demonstrated that Shp2 deficiency inhibited DC migration both in vitro and in vivo and loss of Shp2 significantly suppressed the development of asthma induced by house dust mite(HDM).Further analysis showed that the absence of Shp2 in DCs increased phosphorylation of p115 RhoGEF and augmented the activity of Rho-GTP.Increased Rho-GTP activity promoted phosphorylation of myosin light-chain(MLC),cofilin and Pyk2,consequently resulting in impaired DC migration.In addition,Shp2 knockout in mice does not impact the expression of C-C chemokine receptor type7(CCR7).Blocking Shp2 has no direct influence on DC antigen uptake,maturation,and antigen presentation.In conclusion,we define a novel role of Shp2 in regulating DC migration by mediating p115 RhoGEF/Rho signaling,and our findings provide important implications for the pathogenesis and therapy of allergic airway diseases.