Receptor for advanced glycation end products (RAGE) - a central mediator of allergic sensitization
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1
Woolcock Institute of Medical Research, Sydney Medical School, The University of Sydney, Australia
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2
School of Biomedical Sciences, The University of Queensland, Australia
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3
Faculty of Pharmacy, The University of Sydney, Australia
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4
School of Pharmacy, The University of Technology Sydney, Australia
Allergic sensitization to house dust mite (HDM) is a significant risk factor associated with asthma onset and progression. Activation of innate pattern-recognition receptors (PRRs) can induce the release of endogenous tissue alarmins that modulate the magnitude of the inflammatory response. RAGE is a PRR with the unique capacity to recognise a diverse repertoire of endogenous alarmins, and can collaborate with toll-like receptor (TLR) 4 (known to ‘sense’ HDM), yet its role in the development of allergic sensitization to HDM and other allergens remains obscure. Here, we report that HDM-induced airway inflammation was diminished in RAGE-deficient mice. Strikingly, the early induction of HDM-induced IL-33 and IL-25 was TLR4-dependent; whereas a second ‘wave’ (persistent expression) of these TH2-instructive cytokines was regulated downstream of RAGE activation. HDM sensitization also induced nuclear to cytoplasmic translocation of endogenous alarmin, high mobility group box-1 (HMGB1), and elevated levels in bronchoalveolar lavage fluid. Like innate cytokines, the early HMGB1 activation was TLR4-dependent and later on sustained via RAGE signalling. Moreover the magnitude of the TH2 immune response was abolished when HMGB1 was neutralized, implicating the functional role of HMGB1. With evidence that RAGE is engaged secondary to TLR4, we hypothesised that it might potentially function as a common pathway down-stream of various PRRs involved in initial allergen recognition/sensing. Of note, we demonstrated that RAGE-deficient mice were also protected against cockroach-extract induced allergic inflammation and had attenuated levels of HMGB1. Together, these studies address HMGB1-RAGE signalling as a critical innate mechanism of allergic sensitization and development of airway inflammation.
Acknowledgements
This work was supported by research funding from The University of Sydney and The University of Technology, Sydney, Australia to Dr Maria B Sukkar. Md Ashik Ullah is supported by an International Postgraduate Research Scholarship (IPRS), The University of Sydney, Australia
Keywords:
House dust mite,
TLR4,
HMGB1,
Allergic Sensitization,
Rage
Conference:
15th International Congress of Immunology (ICI), Milan, Italy, 22 Aug - 27 Aug, 2013.
Presentation Type:
Abstract
Topic:
Innate immunity
Citation:
Ullah
M,
Loh
Z,
Gan
WJ,
Zhang
V,
Hughes
J,
Armour
C,
Phipps
S and
Sukkar
M
(2013). Receptor for advanced glycation end products (RAGE) - a central mediator of allergic sensitization.
Front. Immunol.
Conference Abstract:
15th International Congress of Immunology (ICI).
doi: 10.3389/conf.fimmu.2013.02.00553
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Received:
26 Apr 2013;
Published Online:
22 Aug 2013.
*
Correspondence:
Mr. Md. Ashik Ullah, Woolcock Institute of Medical Research, Sydney Medical School, The University of Sydney, Sydney, Australia, ashik.ullah@qimrberghofer.edu.au