Receptor for advanced glycation endproducts (RAGE) maintains pulmonary structure and regulates the response to cigarette smoke

Abstract

The receptor for advanced glycation endproducts (RAGE) is highly expressed in the lung but its physiological functions in this organ is still not completely understood. To determine the contribution of RAGE to physiological functions of the lung, we analyzed pulmonary mechanics and structure of wildtype and RAGE deficient (RAGE-/-) mice. RAGE deficiency spontaneously resulted in a loss of lung structure shown by an increased mean chord length, increased respiratory system compliance, decreased respiratory system elastance and increased concentrations of serum protein albumin in bronchoalveolar lavage fluids. Pulmonary expression of RAGE was mainly localized on alveolar epithelial cells and alveolar macrophages. Primary murine alveolar epithelial cells isolated from RAGE-/- mice revealed an altered differentiation and defective barrier formation under in vitro conditions. Stimulation of interferone-y (IFNy)-activated alveolar macrophages deficient for RAGE with Toll-like receptor (TLR) ligands resulted in significantly decreased release of proinflammatory cytokines and chemokines. Exposure to chronic cigarette smoke did not affect emphysema-like changes in lung parenchyma in RAGE-/- mice. Acute cigarette smoke exposure revealed a modified inflammatory response in RAGE-/- mice that was characterized by an influx of macrophages and a decreased keratinocyte-derived chemokine (KC) release. Our data suggest that RAGE regulates the differentiation of alveolar epithelial cells and impacts on the development and maintenance of pulmonary structure. In cigarette smoke-induced lung pathology, RAGE mediates inflammation that contributes to lung damage.

Fine mapping of the major bleomycin-induced pulmonary fibrosis susceptibility locus in mice

“…There is also evidence that bleomycin damages epithelial cells in the pulmonary fibrosis process (Jin et al 2018 ), thus genetic variants influencing epithelial cell function could affect susceptibility to fibrosis. For example, Ager encodes a surface protein expressed on the lung epithelium (Wolf et al 2017 ), and candidate gene association studies have reported an increased risk (Yamaguchi et al 2017 ) or no increased risk (Manichaikul et al 2017 ) of the related trait of idiopathic pulmonary fibrosis in patients carrying an AGER minor allele. In addition, Cyp21a1 encodes a hydroxylase expressed in the epithelium of the developing lung (Gilbert et al 2017 ) and deficiencies in this hydroxylase result in congenital adrenal hyperplasia (El-Maouche et al 2017 ), while the product of Tnxb is an extracellular matrix glycoprotein whose variants are associated with the connective tissue fragility of Ehlers–Danlos Syndrome (Chen et al 2016 ; Mao et al 2002 ).…”

The role of RAGE in host pathology and crosstalk between RAGE and TLR4 in innate immune signal transduction pathways

“…53 Alveolar epithelial cells isolated from RAGEdeficient mice are also impaired, exhibiting defective barrier formation. 53 In a model of acute lung injury induced by LPS, leukocyte infiltration into the lung was decreased, suggesting that RAGE regulates lung dynamics through down-regulation of ion channels and/or increased tight junction proteins. 39 This may also explain why RAGE-deficient mice have diminished development of smoke-induced emphysema.…”

“…In mice lacking RAGE, the structure of the lung is altered, resulting in increased respiratory system compliance, decreased respiratory system elastance, and increased concentrations of serum protein albumin in bronchoalveolar lavage fluid (BALF) 53 . Alveolar epithelial cells isolated from RAGE‐deficient mice are also impaired, exhibiting defective barrier formation 53 .…”

“…In mice lacking RAGE, the structure of the lung is altered, resulting in increased respiratory system compliance, decreased respiratory system elastance, and increased concentrations of serum protein albumin in bronchoalveolar lavage fluid (BALF) 53 . Alveolar epithelial cells isolated from RAGE‐deficient mice are also impaired, exhibiting defective barrier formation 53 . In a model of acute lung injury induced by LPS, leukocyte infiltration into the lung was decreased, suggesting that RAGE regulates lung dynamics through down‐regulation of ion channels and/or increased tight junction proteins 39 .…”

“…For example, RAGE has been shown to facilitate phagocytosis of DNA into host endosomes and thereby enhance TLR9‐dependent NF‐κB activation 16 . Additionally, RAGE has been shown to regulate the expression of TLR4 and TLR2 in RAW 264.7 cells 82 and the response to TLR ligands in IFN‐γ‐stimulated alveolar macrophages 53 . However, the following section will focus on evidence that supports direct cross‐talk between RAGE ligands and TLRs.…”