title: CARMA3 Is Critical for the Initiation of Allergic Airway Inflammation.
abstract: Innate immune responses to allergens by airway epithelial cells (AECs) help initiate and propagate the adaptive immune response associated with allergic airway inflammation in asthma. Activation of the transcription factor NF-κB in AECs by allergens or secondary mediators via G protein-coupled receptors (GPCRs) is an important component of this multifaceted inflammatory cascade. Members of the caspase recruitment domain family of proteins display tissue-specific expression and help mediate NF-κB activity in response to numerous stimuli. We have previously shown that caspase recruitment domain-containing membrane-associated guanylate kinase protein (CARMA)3 is specifically expressed in AECs and mediates NF-κB activation in these cells in response to stimulation with the GPCR agonist lysophosphatidic acid. In this study, we demonstrate that reduced levels of CARMA3 in normal human bronchial epithelial cells decreases the production of proasthmatic mediators in response to a panel of asthma-relevant GPCR ligands such as lysophosphatidic acid, adenosine triphosphate, and allergens that activate GPCRs such as Alternaria alternata and house dust mite. We then show that genetically modified mice with CARMA3-deficient AECs have reduced airway eosinophilia and proinflammatory cytokine production in a murine model of allergic airway inflammation. Additionally, we demonstrate that these mice have impaired dendritic cell maturation in the lung and that dendritic cells from mice with CARMA3-deficient AECs have impaired Ag processing. In conclusion, we show that AEC CARMA3 helps mediate allergic airway inflammation, and that CARMA3 is a critical signaling molecule bridging the innate and adaptive immune responses in the lung.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114; Division of Rheumatology, Allergy and Immunology, Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129;
authors.forename: Benjamin
authors.initials: B
authors.lastname: Causton
authors.affiliation: Merck Research Laboratories, Boston, MA 02115;
authors.forename: Ravisankar A
authors.initials: RA
authors.lastname: Ramadas
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114; Division of Rheumatology, Allergy and Immunology, Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129;
authors.forename: Josalyn L
authors.initials: JL
authors.lastname: Cho
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114; Division of Rheumatology, Allergy and Immunology, Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129;
authors.forename: Khristianna
authors.initials: K
authors.lastname: Jones
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114; Center for Regenerative Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114;
authors.forename: Ana
authors.initials: A
authors.lastname: Pardo-Saganta
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114; Center for Regenerative Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114;
authors.forename: Jayaraj
authors.initials: J
authors.lastname: Rajagopal
authors.affiliation: Center for Computational and Integrative Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114; and Gastrointestinal Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114.
authors.forename: Ramnik J
authors.initials: RJ
authors.lastname: Xavier
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114; Division of Rheumatology, Allergy and Immunology, Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129; bmedoff@mgh.harvard.edu.
authors.forename: Benjamin D
authors.initials: BD
authors.lastname: Medoff
mesh_terms: D056704:Adaptive Immunity; D000255:Adenosine Triphosphate / Q000494:pharmacology; D000485:Allergens / Q000276:immunology; D000528:Alternaria / Q000276:immunology; D000818:Animals; D001249:Asthma / Q000139:chemically induced / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D053468:CARD Signaling Adaptor Proteins / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D004847:Epithelial Cells / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D005260:Female; D005786:Gene Expression Regulation; D007113:Immunity, Innate; D008168:Lung / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D008246:Lysophospholipids / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology; D010047:Ovalbumin / Q000276:immunology; D039981:Pyroglyphidae / Q000276:immunology; D015398:Signal Transduction
chemical_list: D000485:Allergens; D053468:CARD Signaling Adaptor Proteins; C498975:Card10 protein, mouse; D016207:Cytokines; D008246:Lysophospholipids; D016328:NF-kappa B; D000255:Adenosine Triphosphate; D010047:Ovalbumin; C032881:lysophosphatidic acid