Abstract
Notch is an evolutionarily conserved signaling family which iteratively exerts pleiotropic functions in cell fate decisions and various physiological processes, not only during embryonic development but also throughout adult life. In the context of the respiratory system, Notch has been shown to regulate ciliated versus secretory lineage differentiation of epithelial progenitor cells and coordinate morphogenesis of the developing lung. Reminiscent of its role in development, the Notch signaling pathway also plays a role in repair of lung injuries by regulation of stem cell activity, cell differentiation, cell proliferation and apoptosis. In addition to functions in embryonic development, cell and tissue renewal and various physiological processes, including glucose and lipid metabolism, Notch signaling has been demonstrated to regulate differentiation of literally almost all T-cell subsets, and impact on elicitation of inflammatory response and its outcome. We have investigated the role of Notch in allergic airway inflammation in both acute and chronic settings. In this mini-review, we will summarize our own work and recent advances on the role of Notch signaling in allergic airway inflammation, and discuss potential applications of the Notch signaling family in therapy for allergic airway diseases.
Highlights
Allergic Airway DiseasesAllergic asthma has long been considered as a genetically predisposed Th2 immune-mediated inflammatory disease and may causally be attributed to impaired regulatory T cell (Treg) immune regulation [1,2,3,4,5,6]
With regard to the role of DLL4-Notch signaling in Treg differentiation, studies using different disease models have shown contradictory results
We found Tregs expressed significantly higher levels of Notch ligand DLL4 compared to their T-effector counterparts
Summary
Allergic asthma has long been considered as a genetically predisposed Th2 immune-mediated inflammatory disease and may causally be attributed to impaired regulatory T cell (Treg) immune regulation [1,2,3,4,5,6]. Mast cells can be directly activated by allergens through cross-linking of the surface-bound IgE This causes rapid release of preformed mediators from the mast cells, including histamine, leukotrienes and prostaglandins, resulting in bronchoconstriction and airway mucosa edema due to vasodilatation and plasma exudation, which culminate in symptoms of asthma [8]. New therapies targeting IgE and the canonical Th2 cytokines IL-5, IL-4 and IL-13 have been developed based on knowledge of the molecular mechanisms mediating asthmatic airway inflammation. These targeted immunotherapy, in particular anti-IgE and anti-IL5 antibodies, have been shown to reduce asthma severity and frequency of acute exacerbation and achieve steroid-sparing effect in patients with Th2-skewed asthma endotype [11,12,13,14]. Investigations into the molecular mechanisms of the non-Th2 asthma endotypes or pathways upstream of the Th-skewing stage are mandatory
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