Lunatic Fringe: A key regulator of notch ligand Dll4 mediated Th2 inflammation during viral exacerbation of allergic response. (175.4)

Abstract

Abstract Children exposed to environmental cockroach allergen (CRA) have increased susceptibility to develop chronic pulmonary disorders such as asthma later in their life. Moreover when these children encounter a respiratory viral infection it exacerbates their existing condition. The clinical manifestations include increased mucus production and airway hyperreactivity and peribronchial Th2 inflammation, necessitating immediate hospitalization and frequent recurrent hospital visits. In the present study we examined respiratory syncytial virus (RSV) exacerbated allergic responses. Previous studies showed that notch is required for the development of Th2 responses. However the role of notch ligand-Delta like-4 (Dll4) in viral exacerbation is unknown. Here, using a clinically relevant mouse model of RSV exacerbation an abrogation of mucus production and Th2 responses when Dll4 is blocked was observed. Further, our results from CD4-T cell skewing assays suggest that Dll4 augments IL4 production in Th2 cells in an antigen specific manner. Interestingly, both in vitro and in vivo an existing Th2 environment increased lunatic fringe (L-FNG) expression, a glycosyltransferase that enhances Notch activation by ligands of the Delta-like family, in CD4 T cells. Using loss of function assays and an RNAi approach we show that Dll4 augmented IL4 production is L-FNG dependent. These studies highlight a novel regulatory mechanism involved in Dll4 mediated Th2 responses during viral exacerbation.