The Receptor for Advanced Glycation End Products Is a Central Mediator of Asthma Pathogenesis

Abstract

The receptor for advanced glycation end products (RAGE) is a multiligand receptor that has been shown to contribute to the pathogenesis of diabetes, atherosclerosis, and neurodegeneration. However, its role in asthma and allergic airway disease is largely unknown. These studies use a house dust mite (HDM) mouse model of asthma/allergic airway disease. Respiratory mechanics were assessed and compared between wild-type and RAGE knockout mice. Bronchovascular architecture was assessed with quantitative scoring, and expression of RAGE, immunoglobulins, and relevant cytokines was assessed by standard protein detection methods and/or quantitative RT-PCR. The absence of RAGE abolishes most assessed measures of pathology, including airway hypersensitivity (resistance, tissue damping, and elastance), eosinophilic inflammation, and airway remodeling. IL-4 secretion, isotype class switching, and antigen recognition are intact in the absence of RAGE. In contrast, normal increases in IL-5, IL-13, eotaxin, and eotaxin-2 production are abrogated in the RAGE knockouts. IL-17 indicates complex regulation, with elevated baseline expression in RAGE knockouts, but no induction in response to allergen. Treatment of WT mice with an inhibitor of RAGE markedly reduces inflammation in the HDM model, suggesting that RAGE inhibition may serve as a promising therapeutic strategy. Finally, the results in the HDM model are recapitulated in an ovalbumin model of asthma, suggesting that RAGE plays a role in asthma irrespective of the identity of the allergens involved.

RAGE-Mediated Suppression of Interleukin-10 Results in Enhanced Mortality in a Murine Model of Acinetobacter baumannii Sepsis

“…RAGE is constitutively expressed in the lung and is known to play a role in numerous lung diseases such as acute respiratory distress syndrome, asthma, and pulmonary fibrosis (33)(34)(35). The role of RAGE has been studied in models of murine pneumonia caused by K. pneumoniae and S. pneumoniae with conflicting findings.…”

Pulmonary receptor for advanced glycation end-products promotes asthma pathogenesis through IL-33 and accumulation of group 2 innate lymphoid cells

“…Pulmonary function testing was measured on a flexiVent machine (SCIREQ) with methacholine challenge (0, 0.75, 3.125, 12.5, and 50 mg/mL doses) as previously described (20, 28). …”

“…In the absence of RAGE, mice sensitized and challenged with HDM allergen develop up-regulated expression of IL-4 and a competent antibody response while exhibiting a marked lack of IL-5 and IL-13 expression, airway hyperreactivity, or allergic airway inflammation that was otherwise observed in identically-treated wild type animals (20). Because ILC2s have been shown to be the major producers of IL-5 and IL-13 in inflamed airways following allergen exposure (24), these results implicated RAGE as a potential mediator of ILC2 accumulation in the lung.…”

Maillard Reactions – An Important Factor of the Safety and Quality of Infant Formula

“…Влияние на активность печеночных ферментов; взаимодействие ПРМ с ре-цептором RAGE индуцирует каскад метаболических превращений, ведущих к усилению продукции промоторов воспаления и увеличению окислитель-ного стресса в клетках печени [37][38][39][40] Аллергические заболе-вания Взаимодействие с рецепторами RAGE клеток иммунной системы; RAGE участвует в прайминге, пролиферации и дифференцировке Т-хелперных клеток; ПРМ усиливает аллергенность молочных белков [41][42][43][44][45][46] *ПРМ -продукты реакции Майара.…”

“…Установлена роль оси HMGB1-RAGE в сенсибилизации и развитии ал-лергического воспаления дыхательных путей. Атте-нуированный ответ на ингаляционные аллергены у Rage -/ -мышей может быть вызван значительным уменьшением количества дендритных клеток в лег-ких и опустошением лимфатических узлов [44,45]. Взаимодействие с рецептором RAGE приводит к по-вышению экспрессии интерлейкина IL-33 и накоп-лению лимфоидных клеток врожденного иммунного ответа второго типа (ILC2 клеток) в дыхательных пу-тях, что также стимулирует аллергическое воспале-ние [46].…”