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

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY

卷:134

Article

Ullah, Md Ashik^1,2  Loh, Zhixuan²  Gan, Wan Jun²  Zhang, Vivian²  Yang, Huan³  Li, Jian Hua³  Yamamoto, Yasuhiko⁴  Schmidt, Ann Marie⁵  Armour, Carol L.¹  Hughes, J. Margaret^1,6  Phipps, Simon²  Sukkar, Maria B.^1,7 

[1] Univ Sydney, Woolcock Inst Med Res, Sydney Med Sch, Sydney, NSW 2006, Australia

[2] Univ Queensland, Sch Biomed Sci, Lab Resp Neurosci & Mucosal Immun, Brisbane, Qld, Australia

[3] Feinstein Inst Med Res, Lab Biomed Sci, New York, NY USA

[4] Kanazawa Univ, Grad Sch Med Sci, Dept Biochem & Mol Vasc Biol, Kanazawa, Ishikawa 9201192, Japan

[5] NYU, Langone Med Ctr, Dept Pathol, New York, NY 10003 USA

[6] Univ Sydney, Fac Pharm, Sydney, NSW 2006, Australia

[7] Univ Technol, Grad Sch Hlth, Sch Pharm, Sydney, NSW, Australia

关键词: Asthma;    allergic sensitization;    epithelium;    TLR4;    RAGE;    IL-1 alpha;    HMGB1;    IL-25;    IL-33;    TSLP;   

DOI  :  10.1016/j.jaci.2013.12.1035

来源: Elsevier

【 摘 要 】

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. Objectives: 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-1 alpha, 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. Conclusion: 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.

【 授权许可】

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