TY - JOUR T1 - The HMGB1-RAGE axis is critical in the process of allergic sensitization JF - European Respiratory Journal JO - Eur Respir J VL - 42 IS - Suppl 57 SP - P874 AU - Md Ashik Ullah AU - Loh Zhixuan AU - Gan Wan Jun AU - J. Margaret Hughes AU - Carol Armour AU - Phipps Simon AU - Sukkar Maria Y1 - 2013/09/01 UR - http://erj.ersjournals.com/content/42/Suppl_57/P874.abstract N2 - Allergic sensitization to house dust mite (HDM) is a significant risk factor for asthma onset and progression. Activation of innate pattern-recognition receptors (PRRs) can induce the release of endogenous alarmins that modulate 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, 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 the alarmin, high mobility group box-1 (HMGB1), and elevated levels in bronchoalveolar lavage fluid. Like innate cytokines, 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 its functional role. With evidence that RAGE is engaged secondary to TLR4, we hypothesised that it might function as a common pathway down-stream of various PRRs involved in initial allergen recognition. 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. ER -