TRP and TLR receptors modulate airway responses to diesel exhaust and allergen co-exposure in sensitized participants

Abstract

Background: Environmental co-exposure to traffic related air pollution and allergen is common globally. However, individual responses to these environmental insults remain variable, possibly due to individual gene-environment interactions.

Objective: Determine whether a genetic risk score (GRS) calculated from single nucleotide polymorphisms in lung cell surface receptor genes implicated in mediating inflammatory responses to environmental pollutants modified lung function in individuals exposed to diesel exhaust (DE) and allergen.

Methods: In a randomized crossover study, 13 allergen-sensitized participants were exposed to diesel exhaust (DE; PM_2.5 concentration of 300 µg/m3), particle-depleted diesel exhaust (PDDE), or filtered air (FA) for 2 hours prior to undergoing an inhaled allergen challenge. Blood samples, spirometry, methacholine challenge, and bronchoscopy were performed up to 48 hours after exposures. Transient receptor potential channel (TRPA1 and TRPV1) and toll-like receptor (TLR2 and TLR4) risk alleles were used to construct an unweighted GRS. Effect modification by condition and GRS was determined relative to the baseline FA and saline co-exposure using mixed effect models.

Results: High GRS and allergen was associated with a significant increase in 24 hour airway hyperresponsiveness (AHR) when co-exposed to FA and PDDE (P = 0.04 and 0.02 respectively) but not DE. Increased AHR in FA and PDDE conditions was associated with increased bronchoalveolar macrophages and decreased lymphocytes.

Conclusions: Variant alleles of the TRP and TLR receptors predispose allergen-exposed individuals to increased AHR and changes in airway immune cells.