title: Contrasting roles for the receptor for advanced glycation end-products on structural cells in allergic airway inflammation vs. airway hyperresponsiveness.
abstract: The receptor for advanced glycation end-products (RAGE) is a multiligand receptor that belongs to the immunoglobulin superfamily. RAGE is reported to be involved in various inflammatory disorders; however, studies that address the role of RAGE in allergic airway disease are inconclusive. RAGE-sufficient (RAGE+/+) and RAGE-deficient (RAGE-/-) mice were sensitized to ovalbumin, and airway responses were monitored after ovalbumin challenge. RAGE-/- mice showed reduced eosinophilic inflammation and goblet cell metaplasia, lower T helper type 2 (Th2) cytokine production from spleen and peribronchial lymph node mononuclear cells, and lower numbers of group 2 innate lymphoid cells in the lung compared with RAGE+/+ mice following sensitization and challenge. Experiments using irradiated, chimeric mice showed that the mice expressing RAGE on radio-resistant structural cells but not hematopoietic cells developed allergic airway inflammation; however, the mice expressing RAGE on hematopoietic cells but not structural cells showed reduced airway inflammation. In contrast, absence of RAGE expression on structural cells enhanced innate airway hyperresponsiveness (AHR). In the absence of RAGE, increased interleukin (IL)-33 levels in the lung were detected, and blockade of IL-33 receptor ST2 suppressed innate AHR in RAGE-/- mice. These data identify the importance of RAGE expressed on lung structural cells in the development of allergic airway inflammation, T helper type 2 cell activation, and group 2 innate lymphoid cell accumulation in the airways. RAGE on lung structural cells also regulated innate AHR, likely through the IL-33-ST2 pathway. Thus manipulating RAGE represents a novel therapeutic target in controlling allergic airway responses.
authors.affiliation: Department of Hematology, Oncology, Allergy and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan;
authors.forename: Akihiko
authors.initials: A
authors.lastname: Taniguchi
authors.affiliation: Department of Hematology, Oncology, Allergy and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan; Field of Medical Technology, Okayama University Graduate School of Health Sciences, Okayama, Japan; miyahara@md.okayama-u.ac.jp.
authors.forename: Nobuaki
authors.identifier: http://orcid.org/0000-0002-8616-0886
authors.initials: N
authors.lastname: Miyahara
authors.affiliation: Department of Hematology, Oncology, Allergy and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan;
authors.forename: Koichi
authors.initials: K
authors.lastname: Waseda
authors.affiliation: Department of Hematology, Oncology, Allergy and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan;
authors.forename: Etsuko
authors.initials: E
authors.lastname: Kurimoto
authors.affiliation: Department of Hematology, Oncology, Allergy and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan;
authors.forename: Utako
authors.initials: U
authors.lastname: Fujii
authors.affiliation: Department of Hematology, Oncology, Allergy and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan; Clinical Research Institute, National Hospital Organization Minami-Okayama Medical Center, Okayama, Japan;
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Tanimoto
authors.affiliation: Department of Hematology, Oncology, Allergy and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan;
authors.forename: Mikio
authors.initials: M
authors.lastname: Kataoka
authors.affiliation: Department of Biochemistry and Molecular Vascular Biology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan; and.
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Yamamoto
authors.affiliation: Division of Cell Biology, Department of Pediatrics, National Jewish Health, Denver, Colorado.
authors.forename: Erwin W
authors.initials: EW
authors.lastname: Gelfand
authors.affiliation: Department of Biochemistry and Molecular Vascular Biology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan; and.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yamamoto
authors.affiliation: Department of Hematology, Oncology, Allergy and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan;
authors.forename: Mitsune
authors.initials: M
authors.lastname: Tanimoto
authors.affiliation: Department of Hematology, Oncology, Allergy and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan;
authors.forename: Arihiko
authors.initials: A
authors.lastname: Kanehiro
mesh_terms: D000485:Allergens / Q000008:administration & dosage; D000818:Animals; D001249:Asthma / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D000072179:Interleukin-1 Receptor-Like 1 Protein; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010047:Ovalbumin / Q000008:administration & dosage / Q000276:immunology; D000067759:Receptor for Advanced Glycation End Products / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D018123:Receptors, Interleukin / Q000037:antagonists & inhibitors; D012130:Respiratory Hypersensitivity / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology; D018418:Th2 Cells / Q000276:immunology
chemical_list: C000593873:Ager protein, mouse; D000485:Allergens; D016207:Cytokines; C486189:Il1rl1 protein, mouse; D000072179:Interleukin-1 Receptor-Like 1 Protein; D000067759:Receptor for Advanced Glycation End Products; D018123:Receptors, Interleukin; D010047:Ovalbumin
keywords: RAGE; airway hyperresponsiveness; allergic airway inflammation; asthma