• Md Ashik Ullah, Zhixuan Loh, Wan Jun Gan, Vivian Zhang, Huan Yang, Jian Hua Li, Yasuhiko Yamamoto, Ann Marie Schmidt, Carol L Armour, J Margaret Hughes, Simon Phipps, and Maria B Sukkar.
• 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.
• J. Allergy Clin. Immunol. 2014 Aug 1;134(2):440-50.

BackgroundThe 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.ObjectivesTo determine the requirement for HMGB1 and RAGE, and their relationship with TLR4, in airway sensitization.MethodsTLR4(-/-), 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.ResultsThe 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.ConclusionThe 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.Copyright © 2014 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.

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