Multidimensional Analysis of Lung Lymph Nodes in a Mouse Model of Allergic Lung Inflammation following PM2.5 and Indeno[1,2,3- cd ]pyrene Exposure

Abstract

Background: Ambient particulate matter with an aerodynamic diameter of ( ) is suggested to act as an adjuvant for allergen-mediated sensitization and recent evidence suggests the importance of T follicular helper (Tfh) cells in allergic diseases. However, the impact of exposure and its absorbed polycyclic aromatic hydrocarbon (PAHs) on Tfh cells and humoral immunity remains unknown. Objectives: We aimed to explore the impact of environmental and indeno[1,2,3- cd ]pyrene (IP), a prominent PAH, as a model, on Tfh cells and the subsequent pulmonary allergic responses. Methods: - or IP-mediated remodeling of cellular composition in lung lymph nodes (LNs) was determined by mass cytometry in a house dust mite (HDM)-induced mouse allergic lung inflammation model. The differentiation and function of Tfh cells in vitro were analyzed by flow cytometry, quantitative reverse transcription polymerase chain reaction, enzyme-linked immunosorbent assay, chromatin immunoprecipitation, immunoprecipitation, and western blot analyses. Results: Mice exposed to during the HDM sensitization period demonstrated immune cell population shifts in lung LNs as compared with those sensitized with HDM alone, with a greater number of differentiated Tfh2 cells, enhanced allergen-induced immunoglobulin E (IgE) response and pulmonary inflammation. Similarly enhanced phenotypes were also found in mice exposed to IP and sensitized with HDM. Further, IP administration was found to induce interleukin-21 ( Il21 ) and Il4 expression and enhance Tfh2 cell differentiation in vitro , a finding which was abrogated in aryl hydrocarbon receptor (AhR)-deficient T cells. Moreover, we showed that IP exposure increased the interaction of AhR and cellular musculoaponeurotic fibrosarcoma (c-Maf) and its occupancy on the Il21 and Il4 promoters in differentiated Tfh2 cells. Discussion: These findings suggest that the (IP)–AhR–c-Maf axis in Tfh2 cells was important in allergen sensitization and lung inflammation, thus adding a new dimension in the understanding of Tfh2 cell differentiation and function and providing a basis for establishing the environment–disease causal relationship. https://doi.org/10.1289/EHP11580

Invited Perspective: Environmental Chemical-Sensing AHR Remains an Enigmatic Key Player in Toxicology

“…provide a detailed characterization of immune effects of fine particulate matter [PM with an aerodynamic diameter of ( )] obtained from atmospheric monitoring stations in Taiwan. 3 This contained various polycyclic aromatic hydrocarbons (PAHs), including indeno[1,2,3- cd ]pyrene (IP). 4 They observed that intratracheal administration of or IP alone exacerbated pathology and modulated immune responses by using a mouse model for house dust mite (HDM)-mediated asthma.…”

“… 4 They observed that intratracheal administration of or IP alone exacerbated pathology and modulated immune responses by using a mouse model for house dust mite (HDM)-mediated asthma. 3 Importantly, they used mass cytometry to determine that both and IP exposure increased the percentage and number of T follicular helper (Tfh) cells in the lung-draining lymph nodes. In addition, the enhancement in Tfh cells was dependent on AHR expression in T cells, at least for .…”

“… 5 Therefore, it was important that they also demonstrated that IP enhanced levels of HDM-specific immunoglobulin E (IgE) and IgG in serum. 3 Previously, they had demonstrated that IP-mediated exacerbation in a mouse ovalbumin-induced model of allergic lung inflammation was attenuated with the AHR antagonist CH223191. 4 …”

“…Indeed, the two juxtaposed studies used different disease models, with Houser and Lawrence 6 using a replicating pathogen (influenza virus), and Liu et al. 3 using a representative allergen (HDM).…”

“…The demonstration that two environmentally relevant ligands exhibit opposite effects on the Tfh cell population (i.e., IP enhanced and TCDD suppressed) 3 , 6 could also be explained by differences in AHR affinity, ligand metabolism, or bioavailability. IP was determined to have a half maximal effective concentration ( ) for induction of ethoxyresorufin- -deethylase, an enzymatic measure of AHR-responsive cytochrome P4501A1, of , which is 10,000 times less effective than TCDD.…”