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

• Published in: Scientific reports Vol. 7; no. 1; p. 43535
• Main Authors: Huang, Miao-Tzu, Chen, Yi-Lien, Lien, Chia-I, Liu, Wei-Liang, Hsu, Li-Chung, Yagita, Hideo, Chiang, Bor-Luen
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 06.03.2017; Nature Publishing Group
• Subjects: 13/21; 13/31; 38/109; 38/77; 631/250/256/2516; 64/60; 692/699/1785/31; 9/10; Allergens - immunology; Animals; Antibodies - blood; Antibodies - immunology; Asthma - genetics; Asthma - immunology; Asthma - metabolism; Biomarkers; Cytokines - metabolism; Disease Models, Animal; Female; Homeostasis; Humanities and Social Sciences; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - metabolism; Jagged-1 Protein - genetics; Jagged-1 Protein - metabolism; Lymphocyte Activation - immunology; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mice; Mice, Transgenic; multidisciplinary; Receptors, Notch - metabolism; Respiratory Hypersensitivity - genetics; Respiratory Hypersensitivity - immunology; Respiratory Hypersensitivity - metabolism; Science; Signal Transduction; T-Lymphocyte Subsets - immunology; T-Lymphocyte Subsets - metabolism
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep43535

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.