Vehicular exhaust particles promote allergic airway inflammation through an aryl hydrocarbon receptor–notch signaling cascade

Abstract

Background Traffic-related particulate matter (PM) has been linked to heightened incidence of asthma and allergic diseases. However, molecular mechanisms by which PM exposure promote allergic diseases remain elusive. Objective We sought to determine the expression, function and regulation of pathways involved in the promotion by PM of allergic airway inflammation. Methods We employed gene expression transcriptional profiling, in vitro culture assays, and vivo murine models of allergic airway inflammation. Results We identified genes of the Notch pathway, most notably Jagged 1 (Jag1), as targets of PM induction in human monocytes and murine dendritic cells (DCs). PM, especially ultrafine particles (UFP), upregulated T helper cytokine, IgE production and allergic airway inflammation in mice in a Jag1 and Notch-dependent manner especially in the context of the pro-asthmatic IL-4 receptor allele Il4raR576. PM-induced Jag1 expression was mediated by the aryl hydrocarbon receptor (AhR), which bound to and activated AhR response elements in the Jag1 promoter. Pharmacological antagonism of AhR or its lineage-specific deletion in CD11c+ cells abrogated the augmentation of airway inflammation by PM. Conclusion PM activate an AhR-Jag1-Notch cascade to promote allergic airway inflammation in concert with pro-asthmatic alleles.

An asthma-associated IL4R variant exacerbates airway inflammation by promoting conversion of regulatory T cells to TH17-like cells

“…To determine whether the IL-4Rα-R576 mutation elicits T H 17 airway responses in vivo , we employed a house dust mite (HDM)-induced model of airway inflammation 18 . Il4ra R576 mice, homozygous for the IL-4Rα-R576 mutation, exhibited severe airway inflammation as compared to control mice homozygous for the wild-type (WT) IL-4Rα-Q576 residue.…”

Air pollution and allergic diseases

“…Mechanisms by which DEP exposure increases allergen-induced Th2 differentiation have been reviewed elsewhere (98). A recent study using co-cultures of OVA transgenic CD4+ T cells and bone marrow derived dendritic cells (BMDC) pre-exposed to OVA with or without TRAP, demonstrated increased IFNγ, IL4, IL13, and IL17 levels in culture supernatants of OVA+TRAP exposed BMDC compared to BMDC exposed to OVA alone (99) supporting that TRAP exposure directly impacts dendritic cells. Further, TRAP upregulated T H cytokine levels, IgE production, and allergic airway inflammation in mice in a Jagged1- and Notch-dependent manner and TRAP-induced Jagged1 expression was mediated by the AhR, which bound to and activated AhR response elements in the Jag1 promoter (99).…”

Regulatory T cells in allergic diseases

“…This allele is associated with asthma severity, while introduction of the Q576R substitution into the murine IL-4Rα results in exaggerated allergic airway inflammation when the mice are sensitized then challenged in their airways with allergens 125-127 (Fig 6). Signalling via IL-4Rα-Q576R allele does not impact the activation by the IL-4R of its dedicated transcription factor STAT6, and Th2 cell responses promoted via the IL-4R are preserved.…”