RAGE: a new frontier in chronic airways disease

Abstract

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.

S100A8 Induces IL-10 and Protects against Acute Lung Injury

“…RAGE is highly expressed in (33), and TLR4 plays an important role in ALI. In this article, we report, to our knowledge, the first in-depth study of effects of administering S100A8 to a healthy organ.…”

All the “RAGE” in lung disease: The receptor for advanced glycation endproducts (RAGE) is a major mediator of pulmonary inflammatory responses

“…Enhanced expression of RAGE and its ligands [19,128–135], and decreased sRAGE expression in the lungs [135–140] suggests RAGE signaling contributes to the chronic inflammatory response in COPD. Activation of RAGE signaling in response to smoke likely initially evolved as a protective mechanism to promote an inflammatory response against inhaled pollutants; in smokers who are constantly exposed to smoke, however, there is a “tipping point,” at which this response goes unchecked, possibly due to genetic susceptibility factors [141,142]. …”

RAGE deficiency predisposes mice to virus-induced paucigranulocytic asthma

“…This is consistent with the observation that, compared to non-asthmatic individuals, TLR7 function is reduced in adolescents with asthma (Roponen et al, 2010). There is also a growing body of evidence implicating high mobility group box 1 (HMGB1) and the receptor for advanced glycation endproducts (RAGE) in disease development (Sukkar et al, 2012). HMGB1 is an alarmin that acts as a non-histone nuclear protein in quiescent cells.…”