Mechanisms and Consequences of Variable TRPA1 Expression by Airway Epithelial Cells: Effects of TRPV1 Genotype and Environmental Agonists on Cellular Responses to Pollutants in Vitro and Asthma

• Published in: Environmental health perspectives Vol. 131; no. 2; p. 27009
• Main Authors: Rapp, Emmanuel, Lu, Zhenyu, Sun, Lili, Serna, Samantha N, Almestica-Roberts, Marysol, Burrell, Katherine L, Nguyen, Nam D, Deering-Rice, Cassandra E, Reilly, Christopher A
• Format: Journal Article
• Language: English
• Published: United States National Institute of Environmental Health Sciences 01.02.2023; Environmental Health Perspectives
• Subjects: Air Pollutants - toxicity; Air pollution; Air quality management; Airway (Medicine); Analysis; Asthma; Asthma in children; B cells; Child; Development and progression; Dust; Environmental aspects; Environmental Pollutants; Epithelial Cells; Genetic aspects; Health aspects; Humans; Ion channels; Physiological aspects; Pollutants; Protein kinases; RNA; Smoking; Tobacco Smoke Pollution; TRPA1 Cation Channel - genetics; TRPV Cation Channels - genetics; South Korea; Canada; Utah
• ISSN: 0091-6765; 1552-9924
• DOI: 10.1289/EHP11076

Transient receptor potential ankyrin-1 [transient receptor potential cation channel subfamily A member 1 (TRPA1)] and vanilloid-1 [transient receptor potential cation channel subfamily V member 1 (TRPV1)] detect inhaled irritants, including air pollutants and have roles in the development and exacerbation of asthma. This study tested the hypothesis that increased expression of TRPA1, stemming from expression of the loss-of-function (I585V; rs8065080) polymorphic variant by airway epithelial cells may explain prior observations of worse asthma symptom control among children with the I585I/V genotype, by virtue of sensitizing epithelial cells to particulate materials and other TRPA1 agonists. TRP agonists, antagonists, small interfering RNA (siRNA), a nuclear factor kappa light chain enhancer of activated B cells (NF- ) pathway inhibitor, and kinase activators and inhibitors were used to modulate TRPA1 and TRPV1 expression and function. Treatment of genotyped airway epithelial cells with particulate materials and analysis of asthma control data were used to assess consequences of genotype and variable TRPA1 expression on cellular responses and asthma symptom control among children as a function of voluntarily reported tobacco smoke exposure. A relationship between higher TRPA1 expression and function and lower TRPV1 expression and function was revealed. Findings of this study pointed to a mechanism whereby NF- promoted TRPA1 expression, whereas NF- -regulated nucleotide-binding oligomerization domain, leucine rich repeat and pyrin domain containing 2 (NLRP2) limited expression. Roles for protein kinase C and p38 mitogen activated protein kinase were also demonstrated. Finally, the I585I/V genotype was associated with increased TRPA1 expression by primary airway epithelial cells and amplified responses to selected air pollution particles . However, the I585I/V genotype was not associated with worse asthma symptom control among children exposed to tobacco smoke, whereas other and variants were. This study provides insights on how airway epithelial cells regulate TRPA1 expression, how TRPV1 genetics can affect TRPA1 expression, and that and polymorphisms differentially affect asthma symptom control. https://doi.org/10.1289/EHP11076.