Aryl Hydrocarbon Receptor Protects Lungs from Cockroach Allergen–Induced Inflammation by Modulating Mesenchymal Stem Cells

Abstract

Exposure to cockroach allergen leads to allergic sensitization and increased risk of developing asthma. Aryl hydrocarbon receptor (AhR), a receptor for many common environmental contaminants, can sense not only environmental pollutants but also microbial insults. Mesenchymal stem cells (MSCs) are multipotent progenitor cells with the capacity to modulate immune responses. In this study, we investigated whether AhR can sense cockroach allergens and modulate allergen-induced lung inflammation through MSCs. We found that cockroach allergen treated AhR-deficient (AhR−/−) mice showed exacerbation of lung inflammation when compared to wild-type (WT) mice. In contrast, 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), an AhR agonist, significantly suppressed allergen-induced mouse lung inflammation. MSCs were significantly reduced in cockroach allergen challenged AhR−/− mice as compared to WT mice, but increased in cockroach allergen-challenged WT mice when treated with TCDD. Moreover, MSCs express AhR and AhR signaling can be activated by cockroach allergen with increased expression of its downstream genes, cyp1a1 and cyp1b1. Furthermore, we tracked the migration of intravenously injected GFP+ MSCs and found that cockroach allergen-challenged AhR−/− mice displayed less migration of MSCs to the lungs compared to WT. The AhR mediated MSC migration was further verified by an in vitro Transwell migration assay. Epithelial conditioned medium (ECM) prepared from CRE-challenged epithelial cells significantly induced MSC migrations, which was further enhanced by TCDD. The administration of MSCs significantly attenuated cockroach allergen-induced inflammation, which was abolished by TGFβ1 neutralizing antibody. These results suggest that AhR plays an important role in protecting lungs from allergen-induced inflammation by modulating MSC recruitment and their immune-suppressive activity.

Mannose receptor modulates macrophage polarization and allergic inflammation through miR-511-3p

“…27,28 Briefly, mice were sensitized by means of intratracheal inhalation of 20 µg of CRE (B46; GREER Laboratories, Lenoir, NC) per mouse in 50 µL of PBS after achievement of light anesthesia with isoflurane on days 1, 2, 3, and 14 and challenged on days 20 and 22 with the same amount of CRE. Control mice received PBS during the sensitization and challenge phases.…”

Oxidized CaMKII promotes asthma through the activation of mast cells

“…These MMVVδ mice also produced lower serum titers of CRE-specific IgE and IgG1 than WT counterparts ( Figure 1G). Allergic airway inflammation involves Th2 responses in the lungs (32,33). We found that CRE-treated MMVVδ mice showed much lower concentrations of Th2 cytokines IL-4, IL-5, and IL-13 ( Figure 1H).…”

“…Importantly, our data suggest that MMVVδ protects against allergen-induced AHR and lung inflammation in either CRE-or HDM-induced mouse models of asthma. These allergen-induced mouse models of asthma, particularly the well-established CRE-induced mouse model of asthma in our laboratory (33,37), are relevant to patients with asthma and mimic those asthmatic patients who are allergic to CRE. CRE exposure and sensitization has been identified as one of the strongest risk factors associated with the development, severity, and morbidity of asthma (39)(40)(41).…”

“…These findings indicate that these adoptively transferred BMMCs reached lung and were activated by cockroach antigen challenge in our mouse model. In fact, we have tracked the migration of i.v.-injected GFP + bone marrow-derived mesenchymal stem cells (MSCs) and found a significant amount of the migrated GFP + MSCs in the lung tissues after CRE challenge (33). As expected, these MMVVδ mice with adoptively transferred WT BMMCs, but not MMVVδ, reversed the ameliorated AHR and allergic airway inflammation in MMVVδ mice, suggesting that ox-CaMKIIδ in mast cells is crucial for the CRE-induced allergic inflammation and asthma.…”

“…The CRE-induced asthma mouse model was established as described previously (33,37). Briefly, mice were sensitized by intratracheal inhalation of 20 μg cockroach extract (CRE, B46, GREER Laboratories) in 50 μl of PBS under light anesthesia with isoflurane on days 0-4.…”