{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T17:06:58Z","timestamp":1792256818389,"version":"4.4.0"},"reference-count":55,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,6,6]],"date-time":"2022-06-06T00:00:00Z","timestamp":1654473600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>\n                    The lung epithelial barrier serves as a guardian towards environmental insults and responds to allergen encounter with a cascade of immune reactions that can possibly lead to inflammation. Whether the environmental sensor aryl hydrocarbon receptor (AhR) together with its downstream targets cytochrome P450 (CYP1) family members contribute to the regulation of allergic airway inflammation remains unexplored. By employing knockout mice for AhR and for single CYP1 family members, we found that AhR\n                    <jats:sup>-\/-<\/jats:sup>\n                    and CYP1B1\n                    <jats:sup>-\/-<\/jats:sup>\n                    but not CYP1A1\n                    <jats:sup>-\/-<\/jats:sup>\n                    or CYP1A2\n                    <jats:sup>-\/-<\/jats:sup>\n                    animals display enhanced allergic airway inflammation compared to WT. Expression analysis, immunofluorescence staining of murine and human lung sections and bone marrow chimeras suggest an important role of CYP1B1 in non-hematopoietic lung epithelial cells to prevent exacerbation of allergic airway inflammation. Transcriptional analysis of murine and human lung epithelial cells indicates a functional link of AhR to barrier protection\/inflammatory mediator signaling upon allergen challenge. In contrast, CYP1B1 deficiency leads to enhanced expression and activity of CYP1A1 in lung epithelial cells and to an increased availability of the AhR ligand kynurenic acid following allergen challenge. Thus, differential CYP1 family member expression and signaling\n                    <jats:italic>via<\/jats:italic>\n                    the AhR in epithelial cells represents an immunoregulatory layer protecting the lung from exacerbation of allergic airway inflammation.\n                  <\/jats:p>","DOI":"10.3389\/fimmu.2022.901194","type":"journal-article","created":{"date-parts":[[2022,6,6]],"date-time":"2022-06-06T02:04:37Z","timestamp":1654481077000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":22,"title":["Lung Epithelial CYP1 Activity Regulates Aryl Hydrocarbon Receptor Dependent Allergic Airway Inflammation"],"prefix":"10.3389","volume":"13","author":[{"given":"Francesca","family":"Alessandrini","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renske","family":"de Jong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Wimmer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ann-Marie","family":"Maier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isis","family":"Fernandez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miriam","family":"Hils","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeroen T.","family":"Buters","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tilo","family":"Biedermann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ulrich M.","family":"Zissler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Hoffmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia","family":"Esser-von-Bieren","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carsten B.","family":"Schmidt-Weber","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caspar","family":"Ohnmacht","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,6,6]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-immunol-032713-120245","article-title":"The Aryl Hydrocarbon Receptor: Multitasking in the Immune System","volume":"32","author":"Stockinger","year":"2014","journal-title":"Annu Rev Immunol"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20081438","article-title":"Natural Agonists for Aryl Hydrocarbon Receptor in Culture Medium are Essential for Optimal Differentiation of Th17 T Cells","volume":"206","author":"Veldhoen","year":"2009","journal-title":"J Exp Med"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1126\/science.1214914","article-title":"Natural Aryl Hydrocarbon Receptor Ligands Control Organogenesis of Intestinal Lymphoid Follicles","volume":"334","author":"Kiss","year":"2011","journal-title":"Science"},{"key":"B4","doi-asserted-by":"publisher","first-page":"454","DOI":"10.1016\/j.jaci.2010.12.1082","article-title":"Pollen Metabolome Analysis Reveals Adenosine as a Major Regulator of Dendritic Cell-Primed T(H) Cell Responses","volume":"127","author":"Gilles","year":"2011","journal-title":"J Allergy Clin Immunol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1038\/nature21080","article-title":"Feedback Control of AHR Signalling Regulates Intestinal Immunity","volume":"542","author":"Schiering","year":"2017","journal-title":"Nature"},{"key":"B6","doi-asserted-by":"publisher","first-page":"989","DOI":"10.1016\/j.immuni.2014.04.019","article-title":"Activation of the Aryl Hydrocarbon Receptor Dampens the Severity of Inflammatory Skin Conditions","volume":"40","author":"Di Meglio","year":"2014","journal-title":"Immunity"},{"key":"B7","doi-asserted-by":"publisher","first-page":"491","DOI":"10.1093\/toxsci\/kfr175","article-title":"Activation of the Aryl Hydrocarbon Receptor Suppresses Sensitization in a Mouse Peanut Allergy Model","volume":"123","author":"Schulz","year":"2011","journal-title":"Toxicol Sci"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1172\/JCI65642","article-title":"Coal Tar Induces AHR-Dependent Skin Barrier Repair in Atopic Dermatitis","volume":"123","author":"van den Bogaard","year":"2013","journal-title":"J Clin Invest"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1501198","article-title":"Aryl Hydrocarbon Receptor Protects Lungs From Cockroach Allergen-Induced Inflammation by Modulating Mesenchymal Stem Cells","volume":"195","author":"Xu","year":"2015","journal-title":"J Immunol"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1096\/fj.202001529R","article-title":"Aryl Hydrocarbon Receptor Deficiency Enhanced Airway Inflammation and Remodeling in a Murine Chronic Asthma Model","volume":"34","author":"Chang","year":"2020","journal-title":"FASEB J"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.175.11.7348","article-title":"Effects of Aryl Hydrocarbon Receptor Signaling on the Modulation of TH1\/TH2 Balance","volume":"175","author":"Negishi","year":"2005","journal-title":"J Immunol"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejpb.2010.11.005","article-title":"Stable Dry Powder Inhaler Formulation of Tranilast Attenuated Antigen-Evoked Airway Inflammation in Rats","volume":"77","author":"Kawabata","year":"2011","journal-title":"Eur J Pharm Biopharm"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M113.475624","article-title":"Activation of Aryl Hydrocarbon Receptor (Ahr) by Tranilast, an Anti-Allergy Drug, Promotes miR-302 Expression and Cell Reprogramming","volume":"288","author":"Hu","year":"2013","journal-title":"J Biol Chem"},{"key":"B14","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1016\/j.phrs.2014.10.009","article-title":"Tranilast: A Review of its Therapeutic Applications","volume":"91","author":"Darakhshan","year":"2015","journal-title":"Pharmacol Res"},{"key":"B15","doi-asserted-by":"publisher","first-page":"915","DOI":"10.1016\/j.immuni.2018.09.015","article-title":"Aryl Hydrocarbon Receptor Signaling Cell Intrinsically Inhibits Intestinal Group 2 Innate Lymphoid Cell Function","volume":"49","author":"Li","year":"2018","journal-title":"Immunity"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1014465107","article-title":"Aryl Hydrocarbon Receptor Negatively Regulates Dendritic Cell Immunogenicity via a Kynurenine-Dependent Mechanism","volume":"107","author":"Nguyen","year":"2010","journal-title":"Proc Natl Acad Sci U S A"},{"key":"B17","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1080\/1547691X.2019.1706671","article-title":"Activation of Aryl Hydrocarbon Receptor (AhR) in Mesenchymal Stem Cells Modulates Macrophage Polarization in Asthma","volume":"17","author":"Cui","year":"2020","journal-title":"J Immunotoxicol"},{"key":"B18","doi-asserted-by":"publisher","first-page":"1878","DOI":"10.1016\/j.celrep.2019.10.018","article-title":"Aryl Hydrocarbon Receptor Contributes to the Transcriptional Program of IL-10-Producing Regulatory B Cells","volume":"29","author":"Piper","year":"2019","journal-title":"Cell Rep"},{"key":"B19","doi-asserted-by":"publisher","first-page":"197","DOI":"10.1084\/jem.20160789","article-title":"The Aryl Hydrocarbon Receptor Controls Cell-Fate Decisions in B Cells","volume":"214","author":"Vaidyanathan","year":"2017","journal-title":"J Exp Med"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1038\/jhg.2009.58","article-title":"Genetic Variation of Genes for Xenobiotic-Metabolizing Enzymes and Risk of Bronchial Asthma: The Importance of Gene-Gene and Gene-Environment Interactions for Disease Susceptibility","volume":"54","author":"Polonikov","year":"2009","journal-title":"J Hum Genet"},{"key":"B21","doi-asserted-by":"publisher","first-page":"1643","DOI":"10.1016\/j.jaci.2014.12.1872","article-title":"Prime Role of IL-17A in Neutrophilia and Airway Smooth Muscle Contraction in a House Dust Mite-Induced Allergic Asthma Model","volume":"135","author":"Chesne","year":"2015","journal-title":"J Allergy Clin Immunol"},{"key":"B22","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1093\/toxsci\/kfq024","article-title":"Kynurenic Acid is a Potent Endogenous Aryl Hydrocarbon Receptor Ligand That Synergistically Induces Interleukin-6 in the Presence of Inflammatory Signaling","volume":"115","author":"DiNatale","year":"2010","journal-title":"Toxicol Sci"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.115.064246","article-title":"Indole and Tryptophan Metabolism: Endogenous and Dietary Routes to Ah Receptor Activation","volume":"43","author":"Hubbard","year":"2015","journal-title":"Drug Metab Dispos"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1038\/269713a0","article-title":"Evidence for the Clara Cell as a Site of Cytochrome P450-Dependent Mixed-Function Oxidase Activity in Lung","volume":"269","author":"Boyd","year":"1977","journal-title":"Nature"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1093\/toxsci\/kfj025","article-title":"Preferential Induction of CYP1A1 and CYP1B1 in CCSP-Positive Cells","volume":"89","author":"Chang","year":"2006","journal-title":"Toxicol Sci"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1161\/hh1901.097083","article-title":"Constitutive and Inducible Expression of Cyp1a1 and Cyp1b1 in Vascular Smooth Muscle Cells: Role of the Ahr bHLH\/PAS Transcription Factor","volume":"89","author":"Kerzee","year":"2001","journal-title":"Circ Res"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1093\/carcin\/bgu190","article-title":"Upregulation of CYP1B1 Expression by Inflammatory Cytokines is Mediated by the P38 MAP Kinase Signal Transduction Pathway","volume":"35","author":"Smerdova","year":"2014","journal-title":"Carcinogenesis"},{"key":"B28","doi-asserted-by":"publisher","first-page":"353","DOI":"10.1016\/j.immuni.2018.07.010","article-title":"The Environmental Sensor AHR Protects From Inflammatory Damage by Maintaining Intestinal Stem Cell Homeostasis and Barrier Integrity","volume":"49","author":"Metidji","year":"2018","journal-title":"Immunity"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2018.08.007","article-title":"Clockwork Allergy: How the Circadian Clock Underpins Allergic Reactions","volume":"142","author":"Nakao","year":"2018","journal-title":"J Allergy Clin Immunol"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1172\/JCI93910","article-title":"Circadian Clock Component REV-ERBalpha Controls Homeostatic Regulation of Pulmonary Inflammation","volume":"128","author":"Pariollaud","year":"2018","journal-title":"J Clin Invest"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3599","article-title":"An Epithelial Circadian Clock Controls Pulmonary Inflammation and Glucocorticoid Action","volume":"20","author":"Gibbs","year":"2014","journal-title":"Nat Med"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1165\/rcmb.2010-0027TR","article-title":"Role of Transforming Growth Factor-Beta in Airway Remodeling in Asthma","volume":"44","author":"Halwani","year":"2011","journal-title":"Am J Respir Cell Mol Biol"},{"key":"B33","doi-asserted-by":"publisher","first-page":"195ra194","DOI":"10.1126\/scitranslmed.3006448","article-title":"TGFbeta Receptor Mutations Impose a Strong Predisposition for Human Allergic Disease","volume":"5","author":"Frischmeyer-Guerrerio","year":"2013","journal-title":"Sci Transl Med"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-021-00538-7","article-title":"Does the Epithelial Barrier Hypothesis Explain the Increase in Allergy, Autoimmunity and Other Chronic Conditions","volume":"21","author":"Akdis","year":"2021","journal-title":"Nat Rev Immunol"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.96.5.1977","article-title":"Cytochrome P450 CYP1B1 Determines Susceptibility to 7, 12-Dimethylbenz[a]Anthracene-Induced Lymphomas","volume":"96","author":"Buters","year":"1999","journal-title":"Proc Natl Acad Sci U S A"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M113.525659","article-title":"Mitochondrial Targeting of Cytochrome P450 (CYP) 1B1 and its Role in Polycyclic Aromatic Hydrocarbon-Induced Mitochondrial Dysfunction","volume":"289","author":"Bansal","year":"2014","journal-title":"J Biol Chem"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1038\/nature13323","article-title":"Aryl Hydrocarbon Receptor Control of a Disease Tolerance Defence Pathway","volume":"511","author":"Bessede","year":"2014","journal-title":"Nature"},{"key":"B38","doi-asserted-by":"publisher","first-page":"1252","DOI":"10.1016\/j.cell.2020.07.038","article-title":"IL4I1 Is a Metabolic Immune Checkpoint That Activates the AHR and Promotes Tumor Progression","volume":"182","author":"Sadik","year":"2020","journal-title":"Cell"},{"key":"B39","doi-asserted-by":"publisher","first-page":"797","DOI":"10.1093\/intimm\/dxh260","article-title":"Induction and Activation of the Aryl Hydrocarbon Receptor by IL-4 in B Cells","volume":"17","author":"Tanaka","year":"2005","journal-title":"Int Immunol"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1038\/mi.2015.110","article-title":"Interleukin-4 and Interferon-Gamma Orchestrate an Epithelial Polarization in the Airways","volume":"9","author":"Zissler","year":"2016","journal-title":"Mucosal Immunol"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.0903670","article-title":"An Interaction Between Kynurenine and the Aryl Hydrocarbon Receptor can Generate Regulatory T Cells","volume":"185","author":"Mezrich","year":"2010","journal-title":"J Immunol"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1016\/j.jid.2020.11.024","article-title":"CYP1A1 Enzymatic Activity Influences Skin Inflammation Via Regulation of the AHR Pathway","volume":"141","author":"Kyoreva","year":"2020","journal-title":"J Invest Dermatol"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.93.13.6731","article-title":"Characterization of a Murine Ahr Null Allele: Involvement of the Ah Receptor in Hepatic Growth and Development","volume":"93","author":"Schmidt","year":"1996","journal-title":"Proc Natl Acad Sci U S A"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1006\/bbrc.1999.1913","article-title":"Targeted Knockout of Cyp1a1 Gene Does Not Alter Hepatic Constitutive Expression of Other Genes in the Mouse [Ah] Battery","volume":"267","author":"Dalton","year":"2000","journal-title":"Biochem Biophys Res Commun"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.92.11.5134","article-title":"Neonatal Lethality Associated With Respiratory Distress in Mice Lacking Cytochrome P450 1a2","volume":"92","author":"Pineau","year":"1995","journal-title":"Proc Natl Acad Sci U S A"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1111\/all.12642","article-title":"Pollen-Derived Adenosine is a Necessary Cofactor for Ragweed Allergy","volume":"70","author":"Wimmer","year":"2015","journal-title":"Allergy"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2005.11.046","article-title":"Effects of Ultrafine Carbon Particle Inhalation on Allergic Inflammation of the Lung","volume":"117","author":"Alessandrini","year":"2006","journal-title":"J Allergy Clin Immunol"},{"key":"B48","doi-asserted-by":"publisher","first-page":"2513","DOI":"10.3791\/2513","article-title":"Isolation of Mouse Respiratory Epithelial Cells and Exposure to Experimental Cigarette Smoke at Air Liquid Interface","author":"Lam","year":"2011","journal-title":"J Vis Exp"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.21769\/BioProtoc.2013","article-title":"Isolation of Highly Pure Primary Mouse Alveolar Epithelial Type II Cells by Flow Cytometric Cell Sorting","volume":"6","author":"Sinha","year":"2016","journal-title":"Bio Protoc"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0185056","article-title":"BBMerge - Accurate Paired Shotgun Read Merging via Overlap","volume":"12","author":"Bushnell","year":"2017","journal-title":"PloS One"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btq057","article-title":"Fast and SNP-Tolerant Detection of Complex Variants and Splicing in Short Reads","volume":"26","author":"Wu","year":"2010","journal-title":"Bioinformatics"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/bts196","article-title":"RNA-SeQC: RNA-Seq Metrics for Quality Control and Process Optimization","volume":"28","author":"DeLuca","year":"2012","journal-title":"Bioinformatics"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btt656","article-title":"Featurecounts: An Efficient General Purpose Program for Assigning Sequence Reads to Genomic Features","volume":"30","author":"Liao","year":"2014","journal-title":"Bioinformatics"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btp616","article-title":"Edger: A Bioconductor Package for Differential Expression Analysis of Digital Gene Expression Data","volume":"26","author":"Robinson","year":"2010","journal-title":"Bioinformatics"},{"key":"B55","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1093\/nar\/28.1.27","article-title":"KEGG: Kyoto Encyclopedia of Genes and Genomes","volume":"28","author":"Kanehisa","year":"2000","journal-title":"Nucleic Acids Res"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2022.901194\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,6,6]],"date-time":"2022-06-06T02:04:40Z","timestamp":1654481080000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2022.901194\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,6,6]]},"references-count":55,"alternative-id":["10.3389\/fimmu.2022.901194"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2022.901194","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2021.09.20.461064","asserted-by":"object"}]},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,6,6]]},"article-number":"901194"}}