METHODS: We employed in vitro cell culture assays using lung-derived antigen presenting cells and allergen-specific T cells, and in vivo mouse models of allergic airway inflammation that employed myeloid lineage-specific gene deletions, cellular reconstitution approaches and antibody inhibition studies.
RESULTS: We identified lung alveolar macrophage (AM) as the key cellular target of UFP in promoting airway inflammation. Aryl hydrocarbon receptor (AhR)-dependent induction of Jagged 1 (Jag1) expression in AM was necessary and sufficient for the augmentation of allergic airway inflammation by UFP. Furthermore, UFP promoted both Th2 and Th17 cell differentiation of allergen-specific T cells in a Jag1- and Notch4-dependent manner. Moreover, treatment of mice with an anti-Notch 4 antibody abrogated the exacerbation of allergic airway inflammation induced by UFP.
CONCLUSIONS: UFP exacerbate allergic airway inflammation by promoting Jag1-Notch4-dependent interaction between Alveolar Macrophages and Allergen-Specific T cells, leading to augmented Th cell differentiation.