Notch Ligand DLL4 Alleviates Allergic Airway Inflammation via Induction of a Homeostatic Regulatory Pathway

Miao-Tzu Huang,Wei-Liang Liu,Yi-Lien Chen,Chia-I Lien,Hideo Yagita,Li-Chung Hsu,Bor-Luen Chiang

doi:10.1038/srep43535

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. We investigated whether Notch ligands, Jagged1 and DLL4, exert differential effects in OVA-induced allergic asthma. We found that whilst Jagged1 inhibition mitigated Th2-dominated airway inflammation, blockage of DLL4 aggravated the Th2-mediated asthma phenotypes. Additionally, Jagged1 signaling blockage 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 counterbalances Jagged1-induced Th2 responses and facilitates resolution of the airway inflammation to restore homeostasis. These findings uncover a disparate function of Jagged1 and DLL4 in allergic airway diseases, hinting feasibility of Notch ligand-specific targeting in therapy of allergic airway diseases.

Highlights

Allergic asthma is characterized by recurrent inflammatory episodes of the airways towards harmless environmental factors
We found that whilst Jagged[1] contributed to allergic Th2 responses, DLL4 counteracted the Th2 responses via the induction of endogenous Treg-mediated regulatory pathway which conceivably constitutes an inducible and essential homeostatic mechanism during allergic airway inflammation
Our study demonstrated the divergent functions of Jagged[1] and DLL4 in pathogenesis of allergic airway inflammation

Summary

Introduction

Allergic asthma is characterized by recurrent inflammatory episodes of the airways towards harmless environmental factors. Studies have showed that engagement of distinct Notch ligands elicits signals differentially skewing Th subset differentiation In this theory, ligand-specific signaling outcome is conceivably orchestrated by characteristic expression pattern of individual Notch family members under distinct inflammatory circumstances. Ligand-specific signaling outcome is conceivably orchestrated by characteristic expression pattern of individual Notch family members under distinct inflammatory circumstances The latter proposition undoubtedly lays the basis for therapeutic approaches exploiting ligand-specific targeting of Notch signaling pathway. In support of this theory, gain-of-function studies have showed that while DLL engagement induces Th1 differentiation, Jagged generates signals that favor the alternate Th2 fates[12,13,14]. We found that whilst Jagged[1] contributed to allergic Th2 responses, DLL4 counteracted the Th2 responses via the induction of endogenous Treg-mediated regulatory pathway which conceivably constitutes an inducible and essential homeostatic mechanism during allergic airway inflammation

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Conclusion