Receptor for advanced glycation end products and its ligand high-mobility group box-1 mediate allergic airway sensitization and airway inflammation

• Published in: Journal of allergy and clinical immunology Vol. 134; no. 2; pp. 440 - 450.e3
• Main Authors: Ullah, Md Ashik, Loh, Zhixuan, Gan, Wan Jun, Zhang, Vivian, Yang, Huan, Li, Jian Hua, Yamamoto, Yasuhiko, Schmidt, Ann Marie, Armour, Carol L., Hughes, J. Margaret, Phipps, Simon, Sukkar, Maria B.
• Format: Journal Article
• Language: English
• Published: United States Mosby, Inc 01.08.2014; Elsevier Limited
• Subjects: Administration, Intranasal; Adoptive Transfer; Allergens - administration & dosage; Allergens - immunology; allergic sensitization; Allergies; Allergy and Immunology; Animals; Antibodies, Neutralizing - pharmacology; Asthma; Blattellidae - immunology; Chemokines; Dendritic Cells - immunology; Dendritic Cells - pathology; Dendritic Cells - transplantation; Dermatophagoides pteronyssinus; Dermatophagoides pteronyssinus - immunology; epithelium; Gene Expression Regulation; HMGB1; HMGB1 Protein - antagonists & inhibitors; HMGB1 Protein - genetics; HMGB1 Protein - immunology; IL-1α; IL-25; IL-33; Immune system; Inflammation - genetics; Inflammation - immunology; Inflammation - pathology; Interleukin-1alpha - genetics; Interleukin-1alpha - immunology; Interleukin-33; Interleukins - genetics; Interleukins - immunology; Ligands; Lung - drug effects; Lung - immunology; Lung - pathology; Male; Methods; Mice; Mice, Knockout; RAGE; Receptor for Advanced Glycation End Products; Receptors, Immunologic - deficiency; Receptors, Immunologic - genetics; Receptors, Immunologic - immunology; Respiratory Hypersensitivity - genetics; Respiratory Hypersensitivity - immunology; Respiratory Hypersensitivity - pathology; Signal Transduction; Statistical analysis; Studies; TLR4; Toll-Like Receptor 4 - deficiency; Toll-Like Receptor 4 - genetics; Toll-Like Receptor 4 - immunology; TSLP; TSLP; BALF; IL-25; RAGE; HMGB1; IL-1R; IL-1α; IL-33; CCL; Asthma; CR; HDM; PRR; allergic sensitization; epithelium; TLR4; WT; AEC; DAMP; DC; Receptor for advanced glycation end products; Interleukin-1 receptor; Pattern-recognition receptor; Cockroach; Damage-associated molecular pattern; Airway epithelial cell; Dendritic cell; High mobility group box-1; Toll-like receptor 4; House dust mite; Wild type; Chemokine ligand; Bronchoalveolar lavage fluid
• ISSN: 0091-6749; 1097-6825; 1097-6825
• DOI: 10.1016/j.jaci.2013.12.1035

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. To determine the requirement for HMGB1 and RAGE, and their relationship with TLR4, in airway sensitization. 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. 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. 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.