Skip to main content
Download PDF

Variants in transient receptor potential channels and toll-like receptors modify airway responses to allergen and air pollution: a randomized controlled response human exposure study

Respiratory Research volume 24, Article number: 218 (2023) Cite this article

Abstract

Background

Environmental co-exposure to allergen and traffic-related air pollution is common globally and contributes to the exacerbation of respiratory diseases. Individual responses to environmental insults remain variable due to gene-environment interactions.

Objective

This study examined whether single nucleotide polymorphisms (SNPs) in lung cell surface receptor genes modifies lung function change and immune cell recruitment in allergen-sensitized individuals exposed to diesel exhaust (DE) and allergen.

Methods

In this randomized, double-blinded, four-arm, crossover study, 13 allergen-sensitized participants underwent allergen inhalation challenge following a 2-hour exposure to DE, particle-depleted diesel exhaust (PDDE) or filtered air (FA). Lung function tests and bronchoscopic sample collection were performed up to 48 h after exposures. Transient receptor potential channel (TRPA1 and TRPV1) and toll-like receptor (TLR2 and TLR4) risk alleles were used to construct an unweighted genetic risk score (GRS). Exposure-by-GRS interactions were tested using mixed-effects models.

Results

In participants with high GRS, allergen exposure was associated with an increase in airway hyperresponsiveness (AHR) when co-exposed to PDDE (p = 0.03) but not FA or DE. FA and PDDE also were associated with a relative increase in macrophages and decrease in lymphocytes in bronchoalveolar lavage.

Conclusions

TRPs and TLRs variants are associated with increased AHR and altered immune cellularity in allergen-exposed individuals. This effect is blunted by DE exposure, suggesting greater influence of unmeasured gene variants as primary meditators of a particulate-rich co-exposure.

Trial registration

The study was registered with ClinicalTrials.gov on December 20, 2013 (NCT02017431).

Background

Ambient air pollution exposure was associated with nearly 7 million excess deaths worldwide in 20191 and increases in traffic-related air pollution and diesel exhaust (DE) exposures has contributed to increased incidence of asthma 2. Interestingly, there is a broad range in individual responses to air pollutants, a phenomenon that may be explained by underlying variation in genes that mediate cellular responses to environmental pollutants. In particular, single nucleotide polymorphism (SNP) alleles in the transient receptor potential ankyrin 1 (TRPA1), transient receptor potential vanilloid (TRPV1), toll-like receptor 2 (TLR2) and toll-like receptor 4 (TLR4) have been associated with asthma susceptibility and symptom severity 3,4,5,6,7.

A fraction of particulate matter (PM), specifically that under 2.5 μm in size (PM2.5), penetrates deeply into the lungs and is believed to be the most harmful constituent of DE 8. PM contained in DE is thought to interact with cell surface TRPs and TLRs located in lung tissues 3,4,5,6,7, 9. Furthermore, TRP channels expressed in the bronchioles and alveolar epithelium have been shown to increase cytokine expression, airway inflammation, nerve activation, and bronchoconstriction when activated by electrophiles and oxidants in DE 7. Likewise, the pattern recognition receptors TLR2 and 4 expressed on human alveolar macrophages, neutrophils and the lung epithelium are implicated in inflammatory immune responses and have been shown to interact with pollution particulate matter 3, 10, 11.

As TRPs and TLRs mediate physiological responses to external stimuli in the lungs they also play a role in the pathophysiology of asthmatic exacerbation 3, 4, 6, 7. For instance, TRP channels and TLR receptors have been demonstrated to interact with allergens such as house dust mites (HDM) and Timothy grass, leading to increased cytokine expression and inflammation in the nasal and lung mucosa 12,13,14.

Although SNPs in TRPs and TLRs have been previously associated with asthma 3,4,5,6,7, further research is needed to examine if these genetic variants modify lung function change, including airway hyper-responsiveness, in response to common inhaled environmental insults. Specifically, there is a need for controlled human exposure studies to demonstrate the gene-environment interactions. The role for TRPs and TLRs in mediating immune response has been detailed for both allergen and traffic-related air pollution, such as DE 15,16,17,18. However, variants in these receptors’ coding genes and how they may enhance or blunt downstream physiology has not been carefully examined. Our group recently demonstrated that co-exposure to DE and allergen acts synergistically to promote a greater release of inflammatory mediators than allergen exposure alone, specifically increasing monocyte chemoattractant protein (MCP)-1 production and bronchioalveolar lavage (BAL) eosinophils 19. In addition, we found an impairment of lung function after an inhaled allergen challenge in 14 allergen-sensitized participants using spirometry data collected over 48 hours 20. Leveraging samples collected from this completed clinical study, we investigated whether a GRS constructed from TRP and TLR gene variants modulated lung function in response to allergen and DE co-exposure in a prospective, cross-over, direct challenge human clinical trial.

Methods

Participants

In a randomized, cross-over, controlled human exposure study (ClinicalTrial.gov Identifier: NCT02017431), 13 allergen-sensitized participants were recruited and exposed to four co-exposure conditions (Fig. 1 & S1) 20. The mean age of the participants was 30 ± 8 years old with 7 males and 6 females (Table 1). The co-exposures were performed in random order separated by minimum four-week washout period and were as follows: filtered air plus 0.9% saline (FA-S; negative control), FA plus allergen (FA-A), DE diluted to 300 μg/m3 of PM2.5 and allergen (DE-A), and particle-depleted DE and allergen (PDDE-A). PDDE was achieved using high-efficiency particulate absolute filtration and electrostatic precipitation which removed approximately 94% of the PM2.5 to an average of 18.9 μg/m3. In the PDDE gaseous fraction, fewer volatile organic compounds and an increase in NO2 was observed relative to DE 20. Participants were randomized based on computer-generated random ordering of the four different experimental conditions, and the engineers who oversaw the exposures assigned each participant to a randomized sequence. Study participants, coordinators, technicians, outcome assessor, and the study investigators were blinded to the exposure condition. Spirometry was performed before and up to 48 h after each co-exposure. Methacholine challenge was performed 24 h after allergen inhalation. Outcomes assessed for this manuscript were not the primary or secondary outcomes specified in the Clinicaltrails.gov registration 21. Please refer to the study by Wooding et al. 2019 for additional information on study recruitment, equipment, methods, and results of primary endpoints.

Fig. 1
figure 1

Reprinted with permission of the American Thoracic Society. Copyright © 2022 American Thoracic Society. All rights reserved. Wooding et al. 2019, Particle Depletion Does Not Remediate Acute Effects of Traffic-related Air Pollution and Allergen. A Randomized, Double-Blind Crossover Study. Am J Respir Crit Care Med. 200:565–574. The American Journal of Respiratory and Critical Care Medicine is an official journal of the American Thoracic Society

Randomized, double-blinded crossover study design. 13 participants participated in four exposure conditions. Sample collection and spirometry were performed prior to a 2-hour exposure to FA, DE, or PDDE as well as before and for 48 h after 2 min of inhaled saline or allergen challenge. Airway responsiveness (meth PC20) was assessed at 24-hours after exposure using a methacholine challenge.

Full size image
Table 1 Participant characteristics
Full size table

SNP genotyping

SNP genotyping was performed using DNA isolated from whole blood (QIAamp DNA Blood Mini Kit, Qiagen) using TaqMan™ SNP genotyping assays (Thermo Fisher Scientific) on a StepOne Real-Time PCR System (StepOne software v.2.3; Applied Biosystems). Positive control DNA was purchased from Coriell Institute for Medical Research (Catalogue#: HG00103, HG00581, HG00654).

The unweighted genetic risk score (GRS) was calculated from 12 single nucleotide polymorphisms (SNPs) risk alleles. The SNPs were chosen based on significant associations with air pollution and asthma development or severity in gene candidate studies or due to in vitro evidence of their increased activation by pollution particulates 3,4,5,6,7. Subsequently, three SNPs per gene were chosen with minor allele frequencies (MAF) greater than 0.1 based on the highest asthmatic odds ratio or highest in vitro activity to pollution particulates (Table S1). Not all SNPs were non-synonymous mutations. The risk alleles were as follows: T for rs959974 (TRPA1), C for rs7010969 (TRPA1), G for rs222747 (TRPV1), A for rs224534 (TRPV1), T for rs8065080 (TRPV1), C for rs3804099 (TLR2), A for rs4696480 (TLR2), G for rs2737190 (TLR4), C for rs10759932 (TLR4), T for rs1927911 (TLR4), and G for rs10759931 (TLR4). A value of 1 was assigned for each copy of a risk allele therefore giving a possible unweighted genetic risk score between 0 and 22. For rs3804099 and rs10759932, the risk allele was dominant 3, 5 and therefore a value of 2 was assigned to individuals with one or more copies of these alleles.

Electrochemiluminescent multiplex assay

The V-PLEX Human Cytokine 30-Plex Kit (Meso Scale Diagnostics, Rockville, Maryland, USA) was used to assay interleukin (IL)-1α, IL-6, IL-8, tumour necrosis factor (TNF)-α, MCP-1, and macrophage inflammatory protein (MIP)-1β in BAL samples following the manufacturer’s protocol. See Ryu et al., 2020 for detailed methods 22.

Statistical analysis

Statistical analysis was performed with R (version 4.1.2) in RStudio (version 2022.02.3 Build 492). Linear mixed-effects models (R package nlme version 3.1–157) were used to analyze the effect modification by GRS (exposure-by-GRS interaction) on lung function measurements, BAL immune cell proportion as well as BAL immune mediators. Participant ID were included in our model as random effects, and random intercepts were included in the models. A p-value of < 0.05 was considered statistically significant. Meth PC20 were log2 transformed and immune mediator concentrations were log10 transformed to satisfy the normality assumption in our models.

Results

Airway hyperresponsiveness increased with co-exposure to allergen and PDDE, but not DE, in those with higher GRS

The unweighted genetic risk score was derived from 11 risk alleles in the TLR2, TLR4, TRPA1, and TRPV1 genes and ranged from 8 to 16 (mean of 11.1 ± 3.1) (Table 1, Figure S2). A higher GRS theoretically indicated a dysregulation of the four receptors of interest compared to wildtype. The effect of exposure on meth PC20 was significantly modified by GRS for the PDDE-A condition. Specifically, participants with a higher GRS had a greater decrease in meth PC20 in response to allergen and PDDE co exposure (Pint=0.03)(Fig. 2). Although not significant, the exposure-by-GRS interaction for meth PC20 was similar in the FA-A (P = 0.12) and DE-A exposure (P = 0.15). In order to test whether the effect modification by GRS for AHR was not driven by a single SNP, multiple linear mixed-effects models were constructed with multiple GRS each excluding one SNP. Despite the removal of each SNP from the GRS, significant exposure-by-GRS interactions were observed for meth PC20 except for rs224534 (Pint = 0.1 for PDDE-A exposure) (Table S3).

Fig. 2
figure 2

Effects of exposures and GRS on AHR (log2 Meth PC20), BAL macrophages and lymphocyte percentages. Meth PC20 and cell counts measured 24 and 48 h post-exposure respectively. Dashed line indicates no change from FA-S baseline mediated by the GRS or exposure conditions while points indicate individual participant’s changes from baseline. (* p < 0.05 for exposure-by-GRS interaction)

Full size image

Exposure effects on FEV1 at 4 h in response to FA-A was significantly modified by GRS (P = 0.05). FEV1 at 24 h and forced vital capacity (FVC) at 4 and 24 h after exposure were not significantly modified by the GRS (Table S2). Furthermore, there was no significant correlation between the baseline meth PC20 of the FA-S condition and the GRS when compared using linear regression (P = 0.25, Figure S3), indicating that there was no association between GRS and AHR. Moreover, upon adjustment for both the participant’s baseline AHR and sex, the condition-by-GRS interactions remained significant (Table S4). Although, within our model AHR status modified the condition effect on log2 meth PC20, as participants that were not AHR at baseline experienced a greater decrease in meth PC20. This is consistent with the findings of Wooding et al., 201920.

For those with higher GRS, co-exposure to allergen and either FA or PDDE lead to an increase in bronchoalveolar macrophages and decrease in lymphocytes

We previously reported several outcomes that were significantly altered in the BAL, in particular % eosinophils were significantly increased by allergen inhalation 19. However, in the context of GRS, the effect of exposure on BAL macrophage abundance in the airways was significantly modified for the FA-A and PDDE-A conditions (Pint = 0.01 and 0.01, Fig. 2.). An increase in the participant’s calculated GRS corresponded with greater increase in the percentage of lung macrophages in BAL at 48 h post-exposure. Similarly, GRS significantly modified the change in percent lymphocytes in BAL following FA-A and PDDE-A exposures (Pint = 0.02 and 0.02, Fig. 2.). There was no significant effect modification by GRS for macrophages or lymphocytes in the DE-A condition (Pint = 0.67 and 0.86, Fig. 2.) Likewise, there was no significant exposure-by-GRS interaction for bronchoalveolar recruitment of neutrophils or eosinophils in any condition relative to FA-S baseline (Table S2).

In participants with higher GRS, exposure-induced immune mediators were reduced at 48 h in the allergen and DE co-exposure relative to the baseline FA and allergen co-exposure condition

In DE-A and PDDE-A, the effect of exposure on MCP-1 was significantly modified by GRS (Pint <0.01 and 0.05) as an increasing GRS corresponded with smaller accumulation of MCP-1 protein abundance in BAL. For the DE-A condition, in addition to the MCP-1, the effect of exposure was significantly modified by GRS for IL-1α, IL-6, and TNFα (P = 0.01, 0.04, and 0.04). An increasing GRS corresponded with less accumulation of these immune mediators at 48 h post-exposure.

Discussion

Due to the world’s continued reliance on diesel engines and particulate-filtering technology in the transportation sector, co-exposure to DE or PDDE and an environmental allergen is commonplace. This post-hoc study provided an interesting opportunity to provide insight on potential mechanisms by which individual genotypes may be influencing exposure-response phenotypes. However, our present work is a secondary analysis not outlined in our primary design. Therefore, our report is exploratory and hypothesis-generating. Accordingly, we did not perform multiplicity adjustments. Our group has previously demonstrated that co-exposure to allergen and DE or PDDE increases AHR in individuals 20. Nevertheless, research beyond the published primary endpoints of this clinical study is warranted to elucidate individual differences in the responses to environmental insults arising from gene-environment interactions. The current study, for the first time, demonstrates that GRS constructed from SNPs in TRP and TLR genes are associated with a change in AHR and lung macrophage abundance in response to allergen-alone exposure and co-exposure of allergen and diesel exhaust with PM reduction technology applied. Furthermore, co-exposure to allergen and DE was associated with a marginal, but not statistically significant, increased AHR. Importantly, our results are consistent with a model where the effect modification by GRS on meth PC20 is driven primarily by exposure to allergen.

The GRS was derived from risk alleles in TRPA1, TRPV1, TLR2 and TLR4 that either confer an increased in vitro activity (rs222747 and rs224534) or were related to asthmatic prevalence and symptoms in gene candidate studies 3,4,5,6,7. In those with higher GRS, allergen-alone exposure or co-exposure to allergen and PDDE was associated with an increase in AHR and correspondingly an increase in percent macrophages and a decrease in percent lymphocytes in BAL. The TLR receptor is an important inducer of NF-κB signalling that plays a large role in generating an innate immune response 23, 24. Therefore its activation by allergen or PDDE, especially in those genetically predisposed, could explain the observed increase in macrophage recruitment. Macrophages are involved in allergic inflammation, asthma and AHR. Lung macrophages have been shown to be activated through Th2 signalling 25 or directly by allergens 26 and contribute to allergic inflammation through the production of immune mediators 26, 27. Therefore, there may be a relationship between the increase in airway responsiveness with increasing GRS and the increased recruitment of macrophages.

Activated macrophages produce IL-1α 28, MCP-129 and MIP-1β 30, and IL-1α signalling causes inflammation and is upregulated during periods of oxidative stress. Likewise, MCP-1 is involved in macrophage migration and MIP-1β is needed for mounting an inflammatory immune response 29, 30. In addition to the immune mediators produced by the activated macrophages, dysregulation of the TRP channels and TLR receptors in the genetically susceptible could cause additional inflammatory cascades. Ligand-bound TLR can lead to the production of IL-1α, IL-1β, IL-6, IL-8, MCP-1 and TNF 23, 31. The activation of TRP channels can also promote TNF-α and IL-8 signalling cascades 32. A higher GRS may therefore indicate a potential importance of TRPs and TLRs in AHR upon co-exposure with allergen and either FA or PDDE.

High GRS participants showed no significant change in AHR or immune cell recruitment in the DE and allergen co-exposure. The exposure-induced production of the immune mediators IL-1α, MCP-1, IL-6, and TNFα was also reduced with increasing GRS in the DE-A condition. This is contrasted by a previous study that determined that DE and allergen co-exposure causes lung inflammation and DE exposure alone increases non-allergic inflammatory markers and MCP-119. Importantly however, the activation of the TRPV1 channel has been shown to impair MCP-1, MIP-2 and IL-6 production in macrophages leading to an anti-inflammatory effect 32, 33. Furthermore, activation of TRPV1 on lipopolysaccharide (LPS)-stimulated macrophages has been shown to inhibit the production of additional inflammatory mediators, namely the inducible nitric oxide synthase, nitric oxide, cyclooxygenase-2 and prostaglandin 32, 34. Therefore it is plausible that the activation of TRPV1 by electrophiles and oxidants in the DE could impair the production of MIP and MCP-1 thereby decreasing lung macrophage recruitment and consequently diminishing AHR. In other terms, the activation of TRPV1 by DE may offset the inflammatory lung response mediated by TLR signaling, IL-1α production and macrophage recruitment. This proposed immunosuppressing effect of TRPV1 was likely not as prominent in the PDDE and allergen co-exposure as the particle-depleting treatment removed 94% of PM2.5 which has both electrophilic and oxidizing properties 35 that interact with the TRP channels. An in vitro approach using air-liquid interface models may be useful in further investigating the interplay between the function of TRPV1 in modulating the inflammatory response to DE.

The current study has several limitations. Firstly, different allergens in varying concentrations were used to challenge the participants. There may be allergen-specific immune reactions that could complicate this study’s findings. Likewise, the BAL was performed at 48 h post-exposure, thereby limiting our ability to analyze more immediate changes in immune cell recruitment. The modest sample size in our study as well as interindividual variability may also be limiting. To assess potential outlier effects, we performed an analysis that removed the participant with the highest GRS score (Table S5). Results for PC20 PDDE-A, MCP-1 DE-A and PDDE-A, and IL-1α, IL-6, and TNFα DE-A remained significant. Furthermore, the construction of our GRS was focused on SNPs related to receptors that may directly interact with PM, however there are several genes that play an indirect role in responding to PM. These include genes in the nuclear factor κB (NF-κB), activator protein 1 (AP-1), and nuclear factor erythroid 2–related factor 2 (Nrf2) pathways that may have risk alleles that modify the effects of particulate-rich co-exposures 36, 37. Finally, there are reasons why treating each SNP equally in terms of quantifying the GRS is suboptimal, particularly due to potential linkage disequilibrium between SNPs in our GRS, however we don’t have sufficient data (such as detailed genetic ancestry) in this context to make appropriate adjustments.

Conclusion

In summary, leveraging a controlled co-exposure to common environmental pollutants and allergens, we assessed the effect of a GRS related to lung inflammation in response to allergen and DE on lung function and cellular recruitment. We determined that increasing GRS was associated with increased AHR and macrophage recruitment when exposed to FA or PDDE and allergen. However, co-exposure to DE and allergen showed no change in AHR or immune cell recruitment and was associated with a decrease in specific immune mediators at 48 h. We theorized that TRPV1 activation in the DE and allergen co-exposure had an immunosuppressive role. This research highlights the need to further unravel the complex interaction between underlying individual genetics and environmental exposures which lead to lung inflammation and contribute to the exacerbation of chronic lung disease.

Data Availability

Data are available upon reasonable request. Deidentified participant data and statistical analysis code are available upon reasonable request to the corresponding author.

Abbreviations

AHR:

Airway hyperresponsiveness

AP-1:

Activator protein 1

BAL:

Bronchioalveolar lavage

DE:

Diesel exhaust

FA:

Filtered air

FEV1 :

Forced expiratory volume in 1 s

FVC:

Forced vital capacity

GRS:

Genetic risk score

MAF:

Minor allele frequency

Meth PC20 :

Provocative concentration of methacholine causing a 20% drop in FEV1

NF-κB:

Nuclear factor κB

Nrf2:

Nuclear factor erythroid 2–related factor 2

PDDE:

Particle-depleted diesel exhaust

PM2.5 :

Particulate matter with aerodynamic diameter less than 2.5 μm

SNP:

Single nucleotide polymorphism

TLR:

Toll-like receptor

TRAP:

Traffic-related air pollution

TRPA1:

Transient receptor potential ankyrin-1

TRPV1:

Transient receptor potential vanilloid-1

References

  1. Murray CJL, Aravkin AY, Zheng P, et al. Global burden of 87 risk factors in 204 countries and territories, 1990–2019: a systematic analysis for the global burden of Disease Study 2019. The Lancet. 2020;396(10258):1223–49. https://doi.org/10.1016/S0140-6736(20)30752-2

    Article  Google Scholar 

  2. Brauer M, Reynolds C, Hystad P. Traffic-related air pollution and health in Canada. CMAJ. 2013;185(18):1557–8. https://doi.org/10.1503/cmaj.121568

    Article  PubMed  PubMed Central  Google Scholar 

  3. Kerkhof M, Postma DS, Brunekreef B, et al. Toll-like receptor 2 and 4 genes influence susceptibility to adverse effects of traffic-related air pollution on childhood asthma. Thorax. 2010;65(8):690–7. https://doi.org/10.1136/thx.2009.119636

    Article  CAS  PubMed  Google Scholar 

  4. Deering-Rice CE, Shapiro D, Romero EG, et al. Activation of transient receptor potential Ankyrin-1 by Insoluble Particulate Material and Association with Asthma. Am J Respir Cell Mol Biol. 2015;53(6):893–901. https://doi.org/10.1165/rcmb.2015-0086OC

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Smit LAM, Siroux V, Bouzigon E, et al. CD14 and toll-like receptor gene polymorphisms, Country Living, and asthma in adults. Am J Respir Crit Care Med. 2009;179(5):363–8. https://doi.org/10.1164/rccm.200810-1533OC

    Article  CAS  PubMed  Google Scholar 

  6. Gallo V, Dijk FN, Holloway JW, et al. TRPA1 gene polymorphisms and childhood asthma. Pediatr Allergy Immunol. 2017;28(2):191–8. https://doi.org/10.1111/pai.12673

    Article  PubMed  Google Scholar 

  7. Deering-Rice CE, Stockmann C, Romero EG, et al. Characterization of transient receptor potential Vanilloid-1 (TRPV1) variant activation by coal fly Ash particles and Associations with altered transient receptor potential Ankyrin-1 (TRPA1) expression and asthma. J Biol Chem. 2016;291(48):24866–79. https://doi.org/10.1074/jbc.M116.746156

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. McCreanor J, Cullinan P, Nieuwenhuijsen MJ, et al. Respiratory Effects of exposure to Diesel Traffic in Persons with Asthma. N Engl J Med. 2007;357(23):2348–58. https://doi.org/10.1056/NEJMoa071535

    Article  CAS  PubMed  Google Scholar 

  9. Robinson RK, Birrell MA, Adcock JJ, et al. Mechanistic link between diesel exhaust particles and respiratory reflexes. J Allergy Clin Immunol. 2018;141(3):1074–1084e9. https://doi.org/10.1016/j.jaci.2017.04.038

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Bauer RN, Diaz-Sanchez D, Jaspers I. Effects of air pollutants on innate immunity: the role of toll-like receptors and nucleotide-binding oligomerization domain–like receptors. J Allergy Clin Immunol. 2012;129(1):14–24. https://doi.org/10.1016/j.jaci.2011.11.004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Becker S, Fenton MJ, Soukup JM. Involvement of Microbial Components and toll-like receptors 2 and 4 in cytokine responses to Air Pollution particles. Am J Respir Cell Mol Biol. 2002;27(5):611–8. https://doi.org/10.1165/rcmb.4868

    Article  CAS  PubMed  Google Scholar 

  12. Ryu JH, Yoo JY, Kim MJ, et al. Distinct TLR-mediated pathways regulate house dust mite–induced allergic disease in the upper and lower airways. J Allergy Clin Immunol. 2013;131(2):549–61. https://doi.org/10.1016/j.jaci.2012.07.050

    Article  CAS  PubMed  Google Scholar 

  13. Schiffers C, Hristova M, Habibovic A, et al. The transient receptor potential Channel Vanilloid 1 is critical in Innate Airway epithelial responses to protease allergens. Am J Respir Cell Mol Biol. 2020;63(2):198–208. https://doi.org/10.1165/rcmb.2019-0170OC

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Röschmann K, Farhat K, König P, Suck R, Ulmer AJ, Petersen A. Timothy grass pollen major allergen Phl p 1 activates respiratory epithelial cells by a non-protease mechanism. Clin Experimental Allergy. 2009;39(9):1358–69. https://doi.org/10.1111/j.1365-2222.2009.03291.x

    Article  CAS  Google Scholar 

  15. Backaert W, Steelant B, Hellings PW, Talavera K, Van Gerven L. A TRiP through the Roles of transient receptor potential cation channels in type 2 Upper Airway inflammation. Curr Allergy Asthma Rep. 2021;21(3):20. https://doi.org/10.1007/s11882-020-00981-x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Prescott SL. Allergy takes its toll: the role of toll-like receptors in Allergy Pathogenesis. World Allergy Organization Journal. 2008;1(1):4–8. https://doi.org/10.1097/wox.0b013e3181625d9f

    Article  PubMed  PubMed Central  Google Scholar 

  17. Inoue K, Takano H, Yanagisawa R, et al. The role of toll-like receptor 4 in airway inflammation induced by diesel exhaust particles. Arch Toxicol. 2006;80(5):275–9. https://doi.org/10.1007/s00204-005-0040-6

    Article  CAS  PubMed  Google Scholar 

  18. Akopian AN, Fanick ER, Brooks EG. TRP channels and traffic-related environmental pollution-induced pulmonary disease. Semin Immunopathol. 2016;38(3):331–8. https://doi.org/10.1007/s00281-016-0554-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Carlsten C, Blomberg A, Pui M, et al. Diesel exhaust augments allergen-induced lower airway inflammation in allergic individuals: a controlled human exposure study. Thorax. 2016;71(1):35–44. https://doi.org/10.1136/thoraxjnl-2015-207399

    Article  PubMed  Google Scholar 

  20. Wooding DJ, Ryu MH, Hüls A, et al. Particle depletion does not remediate Acute Effects of Traffic-related Air Pollution and Allergen. A Randomized, double-blind crossover study. Am J Respir Crit Care Med. 2019;200(5):565–74. https://doi.org/10.1164/rccm.201809-1657OC

    Article  CAS  PubMed  Google Scholar 

  21. Air Pollution and Allergens - Attenuation of Health Effects Particle Reduction. - Full Text View - ClinicalTrials.gov. Accessed May 1, 2023. https://clinicaltrials.gov/ct2/show/NCT02017431?term=02017431&draw=2&rank=1.

  22. Ryu MH, Lau KSK, Wooding DJ, Fan S, Sin DD, Carlsten C. Particle depletion of diesel exhaust restores allergen-induced lung-protective surfactant protein D in human lungs. Thorax. 2020;75(8):640–7. https://doi.org/10.1136/thoraxjnl-2020-214561

    Article  PubMed  Google Scholar 

  23. Schjenken JE, Glynn DJ, Sharkey DJ, Robertson SA. TLR4 signaling is a major mediator of the female tract response to seminal fluid in Mice1. Biol Reprod. 2015;93(3). https://doi.org/10.1095/biolreprod.114.125740

  24. Takeda K, Akira S. Roles of toll-like receptors in innate immune responses: toll-like receptors in innate immunity. Genes Cells. 2001;6(9):733–42. https://doi.org/10.1046/j.1365-2443.2001.00458.x

    Article  CAS  PubMed  Google Scholar 

  25. Iwasaki N, Terawaki S, Shimizu K et al. Th2 cells and macrophages cooperatively induce allergic inflammation through histamine signaling. Olszewski MA, ed. PLoS ONE. 2021;16(3):e0248158. https://doi.org/10.1371/journal.pone.0248158

  26. Ross EA, Devitt A, Johnson JR, Macrophages. The Good, the bad, and the Gluttony. Front Immunol. 2021;12:708186. https://doi.org/10.3389/fimmu.2021.708186

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Nomura T, Kobayashi T, Iijima K, Bartemes KR, Kita H. Macrophage response to Particulates plays a pivotal role in development of allergic Immune response to Airborne Pollens. J Allergy Clin Immunol. 2019;143(2):AB294. https://doi.org/10.1016/j.jaci.2018.12.898

    Article  Google Scholar 

  28. Malik A, Kanneganti TD. Function and regulation of IL-1α in inflammatory diseases and cancer. Immunol Rev. 2018;281(1):124–37. https://doi.org/10.1111/imr.12615

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Ruytinx P, Proost P, Van Damme J, Struyf S. Chemokine-Induced Macrophage polarization in inflammatory conditions. Front Immunol. 2018;9:1930. https://doi.org/10.3389/fimmu.2018.01930

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Menten P, Wuyts A, Damme JV. Macrophage inflammatory protein-. Published online 2002:27.

  31. Nackiewicz D, Dan M, He W, et al. TLR2/6 and TLR4-activated macrophages contribute to islet inflammation and impair beta cell insulin gene expression via IL-1 and IL-6. Diabetologia. 2014;57(8):1645–54. https://doi.org/10.1007/s00125-014-3249-1

    Article  CAS  PubMed  Google Scholar 

  32. Khalil M, Alliger K, Weidinger C, et al. Functional role of transient receptor potential channels in Immune cells and Epithelia. Front Immunol. 2018;9:174. https://doi.org/10.3389/fimmu.2018.00174

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Zhao JF, Ching LC, Kou YR, et al. Activation of TRPV1 prevents OxLDL-Induced lipid Accumulation and TNF- α -Induced inflammation in macrophages: role of liver X receptor α. Mediat Inflamm. 2013;2013:1–14. https://doi.org/10.1155/2013/925171

    Article  CAS  Google Scholar 

  34. Kim CS, Kawada T, Kim BS, et al. Capsaicin exhibits anti-inflammatory property by inhibiting IkB-a degradation in LPS-stimulated peritoneal macrophages. Cell Signal. 2003;15(3):299–306. https://doi.org/10.1016/S0898-6568(02)00086-4

    Article  CAS  PubMed  Google Scholar 

  35. Shinyashiki M, Eiguren-Fernandez A, Schmitz DA, et al. Electrophilic and redox properties of diesel exhaust particles. Environ Res. 2009;109(3):239–44. https://doi.org/10.1016/j.envres.2008.12.008

    Article  CAS  PubMed  Google Scholar 

  36. Leikauf GD, Kim SH, Jang AS. Mechanisms of ultrafine particle-induced respiratory health effects. Exp Mol Med. 2020;52(3):329–37. https://doi.org/10.1038/s12276-020-0394-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Yang IA, Fong KM, Zimmerman PV, Holgate ST, Holloway JW. Genetic susceptibility to the respiratory effects of air pollution. Thorax. 2008;63(6):555–63. https://doi.org/10.1136/thx.2007.079426

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We would like to thank the research participants, hospital and research staff who helped in conducting this research study. In particular, we would like to thank Agnes Yuen, Andrew Lee, Carley Schwartz, and Christopher Rider for the data collection, clinical recruitment and logistical support, and advice. We also thank the University of British Columbia Faculty of Medicine FLEX program, Vancouver Coastal Health Research Institute, and the University of British Columbia for institutional support.

Funding

This study was supported by Canadian Institutes of Health Research (CIHR) [grant number MOP123319]; WorkSafe BC [grant number RG2011-OG07]; the AllerGen National Centre for Excellence [grant number 12GxE4], and the Legacy for Airway Health.

Author information

Author notes

  1. Andrew Robinson and Ryan D. Huff are first authors.

Authors and Affiliations

  1. Air Pollution Exposure Laboratory, Division of Respiratory Medicine, Department Medicine, Vancouver Coastal Health Research Institute, The University of British Columbia, Vancouver, BC, Canada

    Andrew Robinson, Ryan D. Huff, Min Hyung Ryu & Chris Carlsten

  2. Channing Division of Network Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, USA

    Min Hyung Ryu

Authors
  1. Andrew Robinson
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ryan D. Huff
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Min Hyung Ryu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Chris Carlsten
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

AR and RDH equally contributed to the preparation of this manuscript. AR and RDH designed the genetic risk score and performed the SNP assays. AR analyzed the genetic score data. Statistical analysis was performed by AR and MHR. RDH and CC conceived of the study. CC acquired funding and provided feedback on the analysis and interpretation of the results. This manuscript has been read and approved by all authors.

Corresponding author

Correspondence to Chris Carlsten.

Ethics declarations

Ethics approval and consent to participate

This study was performed in accordance with the Declaration of Helsinki. This human study was approved by the University of British Columbia research ethics board - approval: H11-01831. The study’s clinical trial registration number is NCT02017431 - registered with ClinicalTrials.gov. Participant registration took place from Jan-2014 to Apr-2017. All adult participants provided written informed consent to participate in this study. Data were collected at the Vancouver General Hospital and Air Pollution Exposure Laboratory, University of British Columbia, Vancouver, BC, Canada.

Consent for publication

Not Applicable.

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Robinson, A., Huff, R.D., Ryu, M.H. et al. Variants in transient receptor potential channels and toll-like receptors modify airway responses to allergen and air pollution: a randomized controlled response human exposure study. Respir Res 24, 218 (2023). https://doi.org/10.1186/s12931-023-02518-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/s12931-023-02518-y

Keywords

Respiratory Research

ISSN: 1465-993X

Contact us