Notch ligands DLL4 and Jagged1 exert differential effects in allergic airway inflammation

Abstract

Abstract Notch is a pleiotropic signaling family that has been implicated in pathogenesis of allergic airway diseases; however, the distinct function of individual Notch ligands remains elusive. By using an OVA-induced murine asthma model, we investigated whether Notch ligands, Jagged1 and DLL4, exert differential effects during allergic airway inflammation. We found that whilst Jagged1 inhibition mitigated Th2-dominated airway inflammation, blockage of DLL4 aggravated the Th2-mediated asthma phenotypes. Additionally, blockage of Jagged1 signaling enhanced IL-17 production and neutrophilic airway infiltration. In vitro, exogenous Jagged1 induced Th2-skewed responses, whereas augmented DLL4 signaling displayed a dual role by promoting expansion of both Tregs and Th17. In vivo, DLL4 blockage impaired Treg differentiation which plausibly resulted in exaggerated asthma phenotypes. On the contrary, administration of DLL4-expressing antigen-presenting cells promoted endogenous Treg expansion and ameliorated the allergic responses. Therefore, whilst Jagged1 induces Th2-skewed inflammation, DLL4 elicits an essential self-regulatory mechanism via Treg-mediated pathway that overcomes Jagged1-induced Th2 responses and facilitates resolution of the airway inflammation. These findings uncover a disparate function of Jagged1 and DLL4 in allergic airway diseases, suggesting the feasibility of Notch ligand-specific targeting in therapy of allergic airway diseases.