Research Of The Role And Mechanism Of Notch Signaling In Food Allergy

Food allergy has become a severe public problem all over the world.However,the specific mechanism still remains unclear.Notch signaling,a highly conserved signaling pathway,has been demonstrated to play a key role in many diseases.However,its role in food allergy has not been studied.In this study,the role of Notch signalng pathway in food allergy was demonstrated by blunting Notch signaling in a food allergy mouse model.Then the role and mechanism of Notch signaling in the sensitization and effect phases of food allergy were further studied.In addition,the immune regulation mechanism of cholera toxin(CT),a common immunoadjuvant,was also explored.The main results and conclusions are as follows:(1)In an ovalbumin-induced food allergy mouse model.after blunting Notch signaling,the levels of serum ovalbumin specific IgE and IgG1,the levels of Th2cytokines were decreased significantly,and allergic clinical features of mice were also alleviated.Meanwhile,the expression of T-bet was significantly increased,whereas the expression of Gata-3 was signific antly reduced.Food allergy was inhibied by bluting Notch signaling through suppressing Th2 polarization,enhancing Thl cell differentiation and promoting Th1/Th2 balance in mice.Notch signaling plays a key role in IgE-mediated food allergy.(2)OVA enhanced the expression of Notch ligand Jagged1 on BMDC signific antly.Jagged1-Notch signaling induced Th2 cell differentiation through enhancing the expression of Gata-3,indicating that Jagged1-Notch signaling pathway may play an important role in the sensitization phase of food allergy.In addition,treatment of Jagged1-Fc enhanced allergic responses significantly through promoting Th2 cell differentiation in mice.Jagged1-Notch signaling induces Th2 cell differentiation,and play a positive regulatory role in the sensitization phase of food allergy.(3)ARBL-21-B cell model was used and Notch signaling was induced by priming with Notch ligands.Notch ligand.Dlll-Fc,increased ?-hexosaminidase release,and cytokines production,including TGF-?,IL-?,IL-4,IL-6,and IL-13 significantly.The mechanism was further studied,Dlll-Notch signaling augmented high-affinity IgE receptorsmediated phosphorylation of MAP Ks through suppressing the expression of Dok-1.Besides,a PSAmouse model was used to confirm the role of Notch signaling in degranulation.Notch ligand Dill enhances RBL-2H3 cell degranulation and cytokine production through a novel Notch/Hesl/Dok-1/MAPKs pathway,suggesting Notch signaling play a key role in the effect phase of food allergy.(4)CT enhanced allergic reaction in mice and enhanced the expression of Notch ligand Jgged2 significantly in small intestine and spleen.Further study found that CT enhanced the expression of Jagged2 on BMDC and induced DC mediated Th2 cell differentiation significantly.However,Jagged2-Notch signaling was unnecessary for its role in Th2 cell differentiation.Besides,Jagged2-Notch signaling was not sufficient for Th2 cell differentiation.In addition,this study also found that CT regulated intestinal flora in mice,increasing TM7 significantly.So the immune regulation mechanism of CT may be related to the effect on intestinal flora.The results indicated that Notch signaling plays an important positive regulatory role in food allergy,which provides new scientific basis for better understanding of the mechanism of food allergy and evidence for finding potential therapeutic targets of food allergy.