The axis of the receptor for advanced glycation endproducts in asthma and allergic airway disease

Abstract

Asthma is a generalized term that describes a scope of distinct pathologic phenotypes of variable severity, which share a common complication of reversible airflow obstruction. Asthma is estimated to affect almost 400 million people worldwide, and nearly ten percent of asthmatics have what is considered "severe" disease. The majority of moderate to severe asthmatics present with a "type 2-high" (T2-hi) phenotypic signature, which pathologically is driven by the type 2 cytokines Interleukin-(IL)-4, IL-5, and IL-13. However, "type 2-low" (T2-lo) phenotypic signatures are often associated with more severe, steroid-refractory neutrophilic asthma. A wide range of clinical and experimental studies have found that the receptor for advanced glycation endproducts (RAGE) plays a significant role in the pathogenesis of asthma and allergic airway disease (AAD). Current experimental data indicates that RAGE is a critical mediator of the type 2 inflammatory reactions which drive the development of T2-hi AAD. However, clinical studies demonstrate that increased RAGE ligands and signaling strongly correlate with asthma severity, especially in severe neutrophilic asthma. This review presents an overview of the current understandings of RAGE in asthma pathogenesis, its role as a biomarker of disease, and future implications for mechanistic studies, and potential therapeutic intervention strategies.

Emerging Role of Phospholipase-Derived Cleavage Products in Regulating Eosinophil Activity: Focus on Lysophospholipids, Polyunsaturated Fatty Acids and Eicosanoids

“…Additionally, LPA is reported to activate non-canonical receptors such as peroxisome proliferator-activated receptor (PPAR)-γ, vanilloid receptor 1 channel as well as the receptor for advanced glycosylation products (RAGE) [ 252 , 253 , 256 , 257 ]. RAGE has been recently identified as a major mediator in inflammatory lung diseases, including asthma [ 266 , 267 , 268 ]. In fact, RAGE has been pinpointed as a critical mediator of T H 2 signaling in the lung (using either small molecule inhibitors (e.g., FPS-ZM1) or mice lacking RAGE expression) [ 69 , 269 ].…”

Overlapping and distinct features of viral and allergen immunity in the human lung

“…For instance, 2 polymorphisms in IL33 are risk factors for development of hay fever as early as 4 years of age (Schrö der et al, 2016), and, more broadly, a meta-analysis of genome-wide polymorphisms associated with development of allergic disease found that mutations in TSLP, IL33, and IL1R1 increase the risk of developing respiratory allergy (Hinds et al, 2013). An altered abundance of RAGE and RAGE ligands has also been observed in sputum of children with moderate to severe asthma, and IL-25 expression is elevated in lung biopsies of allergic asthmatics (Perkins et al, 2020). The release of alarmins during viral infection or allergen exposure acts to activate local immune cell populations and amplify the inflammatory signals downstream of PAMPs.…”

Soluble receptor for advanced glycation end products (sRAGE) and asthma: Mendelian randomisation study

“…To the editor, Of the many immune components involved in asthma pathobiology, recent studies have focused on the potential roles of receptor for advanced glycation end products (RAGE). 1 RAGE is a member of the immunoglobulin superfamily, which serves as a pattern-recognition receptor for many glycated and non-glycated ligands. 1 Membranebound RAGE (mRAGE), through binding with ligands, activates various downstream inflammatory pathways.…”

“…1 RAGE is a member of the immunoglobulin superfamily, which serves as a pattern-recognition receptor for many glycated and non-glycated ligands. 1 Membranebound RAGE (mRAGE), through binding with ligands, activates various downstream inflammatory pathways. 1 By contrast, the cleaved form-soluble RAGE (sRAGE)-functions as a decoy receptor through binding pro-inflammatory ligands destined for mRAGE and hence offers anti-inflammatory effects.…”

“…1 Membranebound RAGE (mRAGE), through binding with ligands, activates various downstream inflammatory pathways. 1 By contrast, the cleaved form-soluble RAGE (sRAGE)-functions as a decoy receptor through binding pro-inflammatory ligands destined for mRAGE and hence offers anti-inflammatory effects. 1 These RAGE pathways are involved in a range of lung diseases (eg, acute respiratory distress syndrome) and are a candidate for targeted therapies.…”