The RAGE against the storm.

A mong the pattern recognition receptors (PRRs), the receptor for advanced glycation end-products (RAGE) has been shown to bind many damage-associated molecular patterns (DAMPs, also known as alarmins). DAMPs are released following tissue damage due to both infectious and non-infectious trauma whereby necrotic cells lose membrane integrity, causing their intracellular contents to leak into the surrounding space. In addition, activated immune cells and stressed structural cells (e.g. those under oxidative stress [1]) can actively secrete alarmins. High-mobility group box 1 (HMGB1), a nuclear protein that regulates transcription, is the prototypical DAMP. Uric acid, DNA, heat-shock proteins (HSPs) and members of the calcium-binding S100 proteins also function as DAMPs [2]. Ultimately, alarmins restore homeostasis with the promotion of tissue repair by: stimulating cell proliferation and migration; recruiting progenitors from the stem cell compartment ; and exerting pro-angiogenic effects [3]. By recruiting and activating PRR-expressing cells of the innate immune system , including dendritic cells, DAMPs also promote adaptive immunity [2, 3]. Indeed, danger signalling might have been the evolutionary force that shaped the immune system [4]. RAGE is a transmembrane multi-ligand receptor belonging to the immunoglobulin superfamily [5]. RAGE binds several ligands, including HMGB1, S100A8/9 and S100A12 (calgranu-lins), advanced glycation end-products (AGEs), and serum amyloid A (SAA). RAGE is highly expressed in the lung, where it is believed to serve a homeostatic function [6]. Indeed, RAGE is considered a marker of alveolar type I (ATI) epithelial cells and, by mediating adherence to collagen-rich surfaces like the basal lamina, it appears to determine the ATI epithelial cell flattened and spread morphology that is important for ensuring effective alveolar gas exchange [7]. RAGE is likely to play a crucial role in lung tissue organisation, since downregulation or loss of RAGE expression leads to increased fibrosis [8] and proliferation and migration of pulmonary fibroblasts and alveolar epithelial cells [9]. This is in agreement with the reduced RAGE expression observed in the lungs of subjects with idiopathic pulmonary fibrosis [8, 9] and in nonsmall cell lung carcinomas [10]. Interestingly, polymorphism of AGER, the gene that encodes RAGE, has been associated with increased airflow obstruction (forced expiratory volume in 1 s (FEV1)/forced vital capacity) in a recent genome-wide association study [11]. Interest in danger signals is growing in the field of respiratory medicine, with emerging clinical evidence implicating DAMPs as potentially important drivers of chronic inflammation. Recently, increased HMGB1 and RAGE expression has been reported in …