The perplexing role of RAGE in pulmonary fibrosis: causality or casualty?

Abstract

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease in which most patients die within 3 years of diagnosis. With an unknown etiology, IPF results in progressive fibrosis of the lung parenchyma, diminishing normal lung function, which results in respiratory failure, and eventually, death. While few therapies are available to reduce disease progression, patients continue to advance toward respiratory failure, leaving lung transplantation the only viable option for survival. As incidence and mortality rates steadily increase, the need for novel therapeutics is imperative. The receptor for advanced glycation endproducts (RAGE) is most highly expressed in the lungs and plays a significant role in a number of chronic lung diseases. RAGE has long been linked to IPF; however, confounding data from both human and experimental studies have left an incomplete and perplexing story. This review examines the present understanding of the role of RAGE in human and experimental models of IPF, drawing parallels to recent advances in RAGE biology. Moreover, this review discusses the role of RAGE in lung injury response, type 2 immunity, and cellular senescence, and how such mechanisms may relate to RAGE as both a biomarker of disease progression and potential therapeutic target in IPF. The reviews of this paper are available via the supplemental material section.

Biomarkers of cellular senescence in idiopathic pulmonary fibrosis

“…An exception is RAGE, which was significantly reduced in participants with IPF and, in LASSO regression models, emerged as the most important biomarker in predicting case status, all three measures of pulmonary function (FVC, DLCO, and FEV1), and health-related QoL. RAGE is a member of the immunoglobulin superfamily of receptors highly expressed in the lung that exists in a membrane-bound form as well as in a soluble form, which acts as a decoy receptor [18]. Consistent with our results, a previous study found reduced plasma soluble RAGE in persons with IPF and other ILDs and a significant association with disease severity [19].…”

“…In the present study, we did not observe an association of RAGE with lung tissue expression of P16, although the combinatorial signature of biomarkers predicting P16 lung expression included RAGE. The role of RAGE in the pathogenesis of IPF, however, is still not fully understood and conflicting results have been reported from murine models of lung fibrosis, underscoring the need of additional studies [18].…”

The UIP/IPF fibroblastic focus is a collagen biosynthesis factory embedded in a distinct extracellular matrix

“…For instance, THY1 is decreased at both the RNA (IPF levels 1 -3) and protein (fibrotic alveoli, FF, and mature scar) level in fibrotic specimens. AGER (the gene for the inflammatory receptor RAGE), is a central mediator of inflammation and is transcriptionally decreased in IPF regions 2 & 3 (not level 1; the most normal), whereas AGER protein is suppressed in all fibrotic regions looked at here [20,81]. Similarly, COL1A1, COL1A2, COL5A1, and COL15A1 were shown to be transcriptionally increased in IPF levels 1 -3, however we only find that these collagen proteins are increased in the FF and mature scar (not the fibrotic alveoli).…”

Pathophysiology of RAGE in inflammatory diseases

“…The RAGE axis is involved in rheumatoid arthritis (192), systemic lupus erythematosus (193), amyotrophic lateral sclerosis (194), inflammatory bowel disease (195), depression (196) and other diseases. In addition, RAGE is involved in the fibrotic process in several organs, such as hepatic fibrosis (19), cardiac fibrosis (197), pulmonary fibrosis (198) and renal fibrosis (199) (Figure 2).…”