title: Receptor for advanced glycation end products and its ligand high-mobility group box-1 mediate allergic airway sensitization and airway inflammation.
abstract: BACKGROUND
  The receptor for advanced glycation end products (RAGE) shares common ligands and signaling pathways with TLR4, a key mediator of house dust mite (Dermatophagoides pteronyssinus) (HDM) sensitization. We hypothesized that RAGE and its ligand high-mobility group box-1 (HMGB1) cooperate with TLR4 to mediate HDM sensitization.
  
  
  OBJECTIVE
  To determine the requirement for HMGB1 and RAGE, and their relationship with TLR4, in airway sensitization.
  
  
  METHODS
  TLR4(-/-), RAGE(-/-), and RAGE-TLR4(-/-) mice were intranasally exposed to HDM or cockroach (Blatella germanica) extracts, and features of allergic inflammation were measured during the sensitization or challenge phase. Anti-HMGB1 antibody and the IL-1 receptor antagonist Anakinra were used to inhibit HMGB1 and the IL-1 receptor, respectively.
  
  
  RESULTS
  The magnitude of allergic airway inflammation in response to either HDM or cockroach sensitization and/or challenge was significantly reduced in the absence of RAGE but not further diminished in the absence of both RAGE and TLR4. HDM sensitization induced the release of HMGB1 from the airway epithelium in a biphasic manner, which corresponded to the sequential activation of TLR4 then RAGE. Release of HMGB1 in response to cockroach sensitization also was RAGE dependent. Significantly, HMGB1 release occurred downstream of TLR4-induced IL-1α, and upstream of IL-25 and IL-33 production. Adoptive transfer of HDM-pulsed RAGE(+/+)dendritic cells to RAGE(-/-) mice recapitulated the allergic responses after HDM challenge. Immunoneutralization of HMGB1 attenuated HDM-induced allergic airway inflammation.
  
  
  CONCLUSIONS
  The HMGB1-RAGE axis mediates allergic airway sensitization and airway inflammation. Activation of this axis in response to different allergens acts to amplify the allergic inflammatory response, which exposes it as an attractive target for therapeutic intervention.
authors: Woolcock Institute of Medical Research, Sydney Medical School, University of Sydney, Sydney, Australia; Laboratory for Respiratory Neuroscience and Mucosal Immunity, School of Biomedical Sciences, University of Queensland, Brisbane, Australia.
authors: Md Ashik
authors: MA
authors: Ullah
authors: Laboratory for Respiratory Neuroscience and Mucosal Immunity, School of Biomedical Sciences, University of Queensland, Brisbane, Australia.
authors: Zhixuan
authors: Z
authors: Loh
authors: Laboratory for Respiratory Neuroscience and Mucosal Immunity, School of Biomedical Sciences, University of Queensland, Brisbane, Australia.
authors: Wan Jun
authors: WJ
authors: Gan
authors: Laboratory for Respiratory Neuroscience and Mucosal Immunity, School of Biomedical Sciences, University of Queensland, Brisbane, Australia.
authors: Vivian
authors: V
authors: Zhang
authors: Laboratory of Biomedical Science, Feinstein Institute for Medical Research, New York, NY.
authors: Huan
authors: H
authors: Yang
authors: Laboratory of Biomedical Science, Feinstein Institute for Medical Research, New York, NY.
authors: Jian Hua
authors: JH
authors: Li
authors: Department of Biochemistry and Molecular Vascular Biology, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan.
authors: Yasuhiko
authors: Y
authors: Yamamoto
authors: Department of Pathology, Langone Medical Centre, New York University, New York, NY.
authors: Ann Marie
authors: AM
authors: Schmidt
authors: Woolcock Institute of Medical Research, Sydney Medical School, University of Sydney, Sydney, Australia.
authors: Carol L
authors: CL
authors: Armour
authors: Woolcock Institute of Medical Research, Sydney Medical School, University of Sydney, Sydney, Australia; Faculty of Pharmacy, University of Sydney, Sydney, Australia.
authors: J Margaret
authors: JM
authors: Hughes
authors: Laboratory for Respiratory Neuroscience and Mucosal Immunity, School of Biomedical Sciences, University of Queensland, Brisbane, Australia. Electronic address: s.phipps@uq.edu.au.
authors: Simon
authors: S
authors: Phipps
authors: Woolcock Institute of Medical Research, Sydney Medical School, University of Sydney, Sydney, Australia; School of Pharmacy, Graduate School of Health, University of Technology, Sydney, Australia. Electronic address: maria.sukkar@uts.edu.au.
authors: Maria B
authors: MB
authors: Sukkar
mesh_terms: D000281:Administration, Intranasal; D019264:Adoptive Transfer; D000485:Allergens / Q000008:administration & dosage / Q000276:immunology*; D000818:Animals; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D020048:Blattellidae / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology / Q000473:pathology / Q000637:transplantation; D040002:Dermatophagoides pteronyssinus / Q000276:immunology; D005786:Gene Expression Regulation; D024243:HMGB1 Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000473:pathology; D053582:Interleukin-1alpha / Q000235:genetics / Q000276:immunology; D000067596:Interleukin-33; D007378:Interleukins / Q000235:genetics / Q000276:immunology; D008168:Lung / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D012130:Respiratory Hypersensitivity / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000172:deficiency / Q000235:genetics / Q000276:immunology
chemical_list: D000485:Allergens; D057134:Antibodies, Neutralizing; D024243:HMGB1 Protein; C582808:HMGB1 protein, mouse; C506535:Il33 protein, mouse; D053582:Interleukin-1alpha; D000067596:Interleukin-33; D007378:Interleukins; C442281:Mydgf protein, mouse; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4
keywords: Asthma; HMGB1; IL-1α; IL-25; IL-33; RAGE; TLR4; TSLP; allergic sensitization; epithelium