Md Ashik Ullah1, Zhixuan Loh2, Wan Jun Gan2, Vivian Zhang2, Huan Yang3, Jian Hua Li3, Yasuhiko Yamamoto4, Ann Marie Schmidt5, Carol L Armour6, J Margaret Hughes7, Simon Phipps8, Maria B Sukkar9. 1. 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. 2. Laboratory for Respiratory Neuroscience and Mucosal Immunity, School of Biomedical Sciences, University of Queensland, Brisbane, Australia. 3. Laboratory of Biomedical Science, Feinstein Institute for Medical Research, New York, NY. 4. Department of Biochemistry and Molecular Vascular Biology, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan. 5. Department of Pathology, Langone Medical Centre, New York University, New York, NY. 6. Woolcock Institute of Medical Research, Sydney Medical School, University of Sydney, Sydney, Australia. 7. Woolcock Institute of Medical Research, Sydney Medical School, University of Sydney, Sydney, Australia; Faculty of Pharmacy, University of Sydney, Sydney, Australia. 8. Laboratory for Respiratory Neuroscience and Mucosal Immunity, School of Biomedical Sciences, University of Queensland, Brisbane, Australia. Electronic address: s.phipps@uq.edu.au. 9. 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.
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. 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-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. 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.
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-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. 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.
Authors: M J Gold; P R Hiebert; H Y Park; D Stefanowicz; A Le; M R Starkey; A Deane; A C Brown; G Liu; J C Horvat; Z A Ibrahim; M B Sukkar; P M Hansbro; C Carlsten; S VanEeden; D D Sin; K M McNagny; D A Knight; J A Hirota Journal: Mucosal Immunol Date: 2015-10-28 Impact factor: 7.313
Authors: Elizabeth A Oczypok; Pavle S Milutinovic; John F Alcorn; Anupriya Khare; Lauren T Crum; Michelle L Manni; Michael W Epperly; Adriane M Pawluk; Anuradha Ray; Tim D Oury Journal: J Allergy Clin Immunol Date: 2015-04-28 Impact factor: 10.793
Authors: Jun Nagai; Barbara Balestrieri; Laura B Fanning; Timothy Kyin; Haley Cirka; Junrui Lin; Marco Idzko; Andreas Zech; Edy Y Kim; Patrick J Brennan; Joshua A Boyce Journal: J Clin Invest Date: 2019-12-02 Impact factor: 14.808
Authors: Stephen R Reeves; Gernot Kaber; Alyssa Sheih; Georgiana Cheng; Mark A Aronica; Mervyn J Merrilees; Jason S Debley; Charles W Frevert; Steven F Ziegler; Thomas N Wight Journal: J Histochem Cytochem Date: 2016-04-28 Impact factor: 2.479