title: 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 with 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 with 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 i.v.-injected GFP(+) MSCs and found that cockroach allergen-challenged AhR(-/-) mice displayed less migration of MSCs to the lungs compared with WT. The AhR-mediated MSC migration was further verified by an in vitro Transwell migration assay. Epithelial conditioned medium prepared from cockroach extract-challenged epithelial cells significantly induced MSC migration, which was further enhanced by TCDD. The administration of MSCs significantly attenuated cockroach allergen-induced inflammation, which was abolished by TGF-β1-neutralizing Ab. 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.
authors.affiliation: Johns Hopkins Asthma and Allergy Center, Johns Hopkins University School of Medicine, Baltimore, MD 21224; Department of Sleep Medicine Center, Nanfang Hospital, Southern Medical University, Guangzhou 510515, People's Republic of China; and.
authors.forename: Ting
authors.initials: T
authors.lastname: Xu
authors.affiliation: Johns Hopkins Asthma and Allergy Center, Johns Hopkins University School of Medicine, Baltimore, MD 21224;
authors.forename: Yufeng
authors.identifier: http://orcid.org/0000-0002-6050-4951
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Johns Hopkins Asthma and Allergy Center, Johns Hopkins University School of Medicine, Baltimore, MD 21224;
authors.forename: Lipeng
authors.initials: L
authors.lastname: Qiu
authors.affiliation: Johns Hopkins Asthma and Allergy Center, Johns Hopkins University School of Medicine, Baltimore, MD 21224;
authors.forename: Danh C
authors.identifier: http://orcid.org/0000-0002-1065-7140
authors.initials: DC
authors.lastname: Do
authors.affiliation: Johns Hopkins Asthma and Allergy Center, Johns Hopkins University School of Medicine, Baltimore, MD 21224;
authors.forename: Yilin
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Department of Orthopedic Surgery, Johns Hopkins University School of Medicine, Baltimore, MD 21224.
authors.forename: Zhuang
authors.initials: Z
authors.lastname: Cui
authors.affiliation: Johns Hopkins Asthma and Allergy Center, Johns Hopkins University School of Medicine, Baltimore, MD 21224;
authors.forename: Heng
authors.identifier: http://orcid.org/0000-0002-3563-2337
authors.initials: H
authors.lastname: Wang
authors.affiliation: Johns Hopkins Asthma and Allergy Center, Johns Hopkins University School of Medicine, Baltimore, MD 21224;
authors.forename: Xiaopeng
authors.initials: X
authors.lastname: Liu
authors.affiliation: Johns Hopkins Asthma and Allergy Center, Johns Hopkins University School of Medicine, Baltimore, MD 21224;
authors.forename: Arjun
authors.identifier: http://orcid.org/0000-0002-4723-5419
authors.initials: A
authors.lastname: Saradna
authors.affiliation: Department of Orthopedic Surgery, Johns Hopkins University School of Medicine, Baltimore, MD 21224.
authors.forename: Xu
authors.initials: X
authors.lastname: Cao
authors.affiliation: Department of Orthopedic Surgery, Johns Hopkins University School of Medicine, Baltimore, MD 21224.
authors.forename: Mei
authors.initials: M
authors.lastname: Wan
authors.affiliation: Johns Hopkins Asthma and Allergy Center, Johns Hopkins University School of Medicine, Baltimore, MD 21224; pgao1@jhmi.edu.
authors.forename: Peisong
authors.initials: P
authors.lastname: Gao
mesh_terms: D000485:Allergens / Q000276:immunology; D000818:Animals; D019138:Antibodies, Blocking / Q000494:pharmacology; D001249:Asthma / Q000209:etiology / Q000517:prevention & control*; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D003058:Cockroaches / Q000276:immunology*; D017077:Culture Media, Conditioned / Q000494:pharmacology; D019363:Cytochrome P-450 CYP1A1; D065633:Cytochrome P-450 CYP1B1; D004847:Epithelial Cells / Q000187:drug effects / Q000276:immunology*; D006967:Hypersensitivity / Q000150:complications / Q000276:immunology*; D007114:Immunization; D019476:Insect Proteins / Q000008:administration & dosage; D059630:Mesenchymal Stem Cells / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D011014:Pneumonia / Q000188:drug therapy; D000072317:Polychlorinated Dibenzodioxins / Q000008:administration & dosage / Q000494:pharmacology; D018336:Receptors, Aryl Hydrocarbon / Q000008:administration & dosage* / Q000819:agonists / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000494:pharmacology
chemical_list: D000485:Allergens; D019138:Antibodies, Blocking; D017077:Culture Media, Conditioned; D019476:Insect Proteins; D000072317:Polychlorinated Dibenzodioxins; D018336:Receptors, Aryl Hydrocarbon; D016212:Transforming Growth Factor beta; C585498:Cyp1b1 protein, mouse; D019363:Cytochrome P-450 CYP1A1; D065633:Cytochrome P-450 CYP1B1