title: Notch Ligand DLL4 Alleviates Allergic Airway Inflammation via Induction of a Homeostatic Regulatory Pathway.
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.
authors.affiliation: Department of Medical Research, National Taiwan University Hospital, Taipei, 100, Taiwan.|Department of Pediatrics, National Taiwan University Hospital, Taipei, 100, Taiwan.|Graduate Institute of Clinical Medicine, School of Medicine, National Taiwan University, Taipei, 100, Taiwan.
authors.forename: Miao-Tzu
authors.initials: MT
authors.lastname: Huang
authors.affiliation: Graduate Institute of Clinical Medicine, School of Medicine, National Taiwan University, Taipei, 100, Taiwan.
authors.forename: Yi-Lien
authors.initials: YL
authors.lastname: Chen
authors.affiliation: Graduate Institute of Molecular Medicine, School of Medicine, National Taiwan University, Taipei, 100, Taiwan.
authors.forename: Chia-I
authors.initials: CI
authors.lastname: Lien
authors.affiliation: Graduate Institute of Clinical Medicine, School of Medicine, National Taiwan University, Taipei, 100, Taiwan.|National Mosquito-Borne Diseases Control Research Center, National Health Research Institutes, Miaoli, 35053, Taiwan.
authors.forename: Wei-Liang
authors.initials: WL
authors.lastname: Liu
authors.affiliation: Graduate Institute of Molecular Medicine, School of Medicine, National Taiwan University, Taipei, 100, Taiwan.
authors.forename: Li-Chung
authors.initials: LC
authors.lastname: Hsu
authors.affiliation: Department of Immunology, Juntendo University School of Medicine, Tokyo, Japan.
authors.forename: Hideo
authors.initials: H
authors.lastname: Yagita
authors.affiliation: Department of Medical Research, National Taiwan University Hospital, Taipei, 100, Taiwan.|Department of Pediatrics, National Taiwan University Hospital, Taipei, 100, Taiwan.|Graduate Institute of Clinical Medicine, School of Medicine, National Taiwan University, Taipei, 100, Taiwan.
authors.forename: Bor-Luen
authors.initials: BL
authors.lastname: Chiang
mesh_terms: D000485:Allergens / Q000276:immunology; D000818:Animals; D000906:Antibodies / Q000097:blood / Q000276:immunology; D001249:Asthma / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015415:Biomarkers; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D006706:Homeostasis; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D000072100:Jagged-1 Protein / Q000235:genetics / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D051880:Receptors, Notch / Q000378:metabolism*; D012130:Respiratory Hypersensitivity / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D015398:Signal Transduction; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism
chemical_list: D000485:Allergens; D000906:Antibodies; D015415:Biomarkers; D016207:Cytokines; D047908:Intracellular Signaling Peptides and Proteins; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; D051880:Receptors, Notch; C064045:delta protein