897:
A Jagged1-Notch4 interaction between Alveolar Macrophages and Allergen-Specific T cells Mediates Airway Inflammation by Ultrafine Particles
Monday, March 5, 2018: 2:30 PM
S230EF (Convention Center)
Hani Harb, , , ,
RATIONALE: Exposure to traffic-related particulate matter (PM) promotes asthma and allergic diseases. However, the precise cellular and molecular mechanisms by which PM exposure acts to mediate these effects remains unclear. We sought to elucidate the cellular targets and signal pathways critical for the augmentation of allergic airway inflammation induced by ambient ultrafine particles (UFP).

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.