RAGE: A new frontier in chronic airways disease

School of Pharmacy, The University of Technology Sydney, NSW, Australia Woolcock Institute of Medical Research, Sydney Medical School, The University of Sydney, NSW, Australia School of Biomedical Sciences and Australian Infectious Diseases Research Centre, The University of Queensland, Qld, Australia Centre for Asthma and Respiratory Disease, Hunter Medical Research Institute, University of Newcastle, NSW, Australia Department of Respiratory and Sleep Medicine, John Hunter Hospital, NSW, Australia Airways Disease Section, National Heart and Lung Institute, Imperial College London, London, UK Faculty of Pharmacy, The University of Sydney, NSW, Australia.
British Journal of Pharmacology (Impact Factor: 4.84). 04/2012; 167(6):1161-1176. DOI: 10.1111/j.1476-5381.2012.01984.x
Source: PubMed


Asthma and chronic obstructive pulmonary disease (COPD) are heterogeneous inflammatory disorders of the respiratory tract characterized by airflow obstruction. It is now clear that the environmental factors that drive airway pathology in asthma and COPD, including allergens, viruses, ozone and cigarette smoke, activate innate immune receptors known as pattern-recognition receptors, either directly or indirectly by causing the release of endogenous ligands. Thus, there is now intense research activity focused around understanding the mechanisms by which pattern-recognition receptors sustain the airway inflammatory response, and how these mechanisms might be targeted therapeutically. One pattern-recognition receptor that has recently come to attention in chronic airways disease is the receptor for advanced glycation end products (RAGE). RAGE is a member of the immunoglobulin superfamily of cell surface receptors that recognizes pathogen- and host-derived endogenous ligands to initiate the immune response to tissue injury, infection and inflammation. Although the role of RAGE in lung physiology and pathophysiology is not well understood, recent genome-wide association studies have linked RAGE gene polymorphisms with airflow obstruction. In addition, accumulating data from animal and clinical investigations reveal increased expression of RAGE and its ligands, together with reduced expression of soluble RAGE, an endogenous inhibitor of RAGE signalling, in chronic airways disease. In this review, we discuss recent studies of the ligand-RAGE axis in asthma and COPD, highlight important areas for future research and discuss how this axis might potentially be harnessed for therapeutic benefit in these conditions.

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Available from: Maria B Sukkar, Feb 18, 2014
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    • "RAGE is also expressed on pulmonary tissues and recent studies have suggested that RAGE and its ligands may play a role in obstructive pulmonary disease [11]. A potential limitation, of our studies, therefore, is that the reduced expression of RAGE on tissue cells could have modified the T cellular responses, perhaps even explaining the changes in cytokine secretion that we observed. "
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    ABSTRACT: The receptor for glycation end products (RAGE) has been previously implicated in shaping the adaptive immune response. RAGE is expressed in T cells after activation and constitutively in T cells from patients with diabetes. The effects of RAGE on adaptive immune responses are not clear: Previous reports show that RAGE blockade affects Th1 responses. To clarify the role of RAGE in adaptive immune responses and the mechanisms of its effects, we examined whether RAGE plays a role in T cell activation in a Th2 response involving ovalbumin (OVA)-induced asthma in mice. WT and RAGE deficient wild-type and OT-II mice, expressing a T cell receptor specific for OVA, were immunized intranasally with OVA. Lung cellular infiltration and T cell responses were analyzed by immunostaining, FACS, and multiplex bead analyses for cytokines. RAGE deficient mice showed reduced cellular infiltration in the bronchial alveolar lavage fluid and impaired T cell activation in the mediastinal lymph nodes when compared with WT mice. In addition, RAGE deficiency resulted in reduced OT-II T cell infiltration of the lung and impaired IFNγ and IL-5 production when compared with WT mice and reduced infiltration when transferred into WT hosts. When cultured under conditions favoring the differentiation of T cells subsets, RAGE deficient T cells showed reduced production of IFNγ but increased production of IL-17. Our data show a stimulatory role for RAGE in T activation in OVA-induced asthma. This role is largely mediated by the effects of RAGE on T cell proliferation and differentiation. These findings suggest that RAGE may play a regulatory role in T cell responses following immune activation.
    Full-text · Article · Apr 2014 · PLoS ONE
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    • "This particular measure is also useful because those infants requiring the most supplemental oxygen for management of respiratory illness are also potentially receiving the highest degree of additional inflammatory insults from oxidant stress. This data is similar to that reported in rodents exposed to hyperoxia during the first week of life [24], and in humans with acute lung injury [25,26]. Alternatively, intracellular RAGE signaling is important for normal lung development and alveolarization [27–29]. "
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    ABSTRACT: Soluble RAGE (sRAGE) has been associated with multiple inflammatory responses including maternal chorioamnionitis and preeclampsia. Analysis of umbilical cord blood levels have also indicated that sRAGE levels in the infant are affected by maternal inflammation. S100b is a ligand for RAGE and increases in circulating S100b levels are associated with poor neurological outcome in preterm infants. The objective of this study was to determine whether sRAGE or s100b levels in plasma samples from extremely preterm infants at the end of the first week of life were correlated with infant morbidities and whether sRAGE and s100b levels at this time point were still associated with maternal inflammation. Plasma samples were collected from 130 preterm infants (≤28 weeks) at days of life 5, 6, or 7. sRAGE and s100b levels were measured by ELISA and data were analyzed by Pearson's correlation or Generalized Estimating Equations. sRAGE was negatively correlated with development of sepsis (p=0.024), the FiO2 requirement of the infant at the time of sampling (p=0.030), as well as maternal preeclampsia (p=0.046), and positively correlated with maternal chorioamnionitis (p=0.006). s100b levels were positively associated with maternal chorioamnionitis (p=0.039). No correlations were observed with other infant morbidities. These data indicate that sRAGE could potentially be a biomarker of early severe inflammatory responses in the preterm infant. However, more studies are needed to confirm the present findings.
    Full-text · Article · Dec 2013 · PLoS ONE
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    • "In contrast, the results of the present study indicate that blocking TLR4 completely inhibited the effect of HMGB1, while blocking RAGE only inhibits 50% of the HMGB1 effect on alveolar scratch wound closure, indicating that these two receptors play an important role in HMGB1 signaling in the alveolar epithelium. Although several studies have reported the potential existence of cross-talk between these receptors [44], further examinations would be required to determine its importance for the observations presented here. "
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    ABSTRACT: High mobility group box 1 (HMGB1) protein is a danger-signaling molecule, known to activate an inflammatory response via TLR4 and RAGE. HMGB1 can be either actively secreted or passively released from damaged alveolar epithelial cells. Previous studies have shown that IL-1β, a critical mediator acute lung injury in humans that is activated by HMGB1, enhances alveolar epithelial repair, although the mechanisms are not fully understood. Herein, we tested the hypothesis that HMGB1 released by wounded alveolar epithelial cells would increase primary rat and human alveolar type II cell monolayer wound repair via an IL-1β-dependent activation of TGF-β1. HMGB1 induced in primary cultures of rat alveolar epithelial cells results in the release of IL-1β that caused the activation of TGF-β1 via a p38 MAPK-, RhoA- and αvβ6 integrin-dependent mechanism. Furthermore, active TGF-β1 accelerated the wound closure of primary rat epithelial cell monolayers via a PI3 kinase α-dependent mechanism. In conclusion, this study demonstrates that HMGB1 released by wounded epithelial cell monolayers, accelerates wound closure in the distal lung epithelium via the IL-1β-mediated αvβ6-dependent activation of TGF-β1, and thus could play an important role in the resolution of acute lung injury by promoting repair of the injured alveolar epithelium.
    Full-text · Article · Oct 2013 · PLoS ONE
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