The multiple faces of RAGE – opportunities for therapeutic intervention in aging and chronic disease

Abstract

Introduction: This review focuses on the multi-ligand receptor of the immunoglobulin superfamily – receptor for advanced glycation endproducts (RAGE). The accumulation of the multiple ligands of RAGE in cellular stress milieux links RAGE to the pathobiology of chronic disease and natural aging.

Areas covered: In this review, we present a discussion on the ligands of RAGE and the implications of these ligand families in disease. We review the recent literature on the role of ligand–RAGE interaction in the consequences of natural aging; the macro- and microvascular complications of diabetes; obesity and insulin resistance; autoimmune disorders and chronic inflammation; and tumors and Alzheimer’s disease. We discuss the mechanisms of RAGE signaling through its intracellular binding effector molecule – the formin DIAPH1. Physicochemical evidence of how the RAGE cytoplasmic domain binds to the FH1 (formin homology 1) domain of DIAPH1, and the consequences thereof, are also reviewed.

Expert opinion: We discuss the modalities of RAGE antagonism currently in preclinical and clinical studies. Finally, we present the rationale behind potentially targeting the RAGE cytoplasmic domain–DIAPH1 interaction as a logical strategy for therapeutic intervention in the pathological settings of chronic diseases and aging wherein RAGE ligands accumulate and signal.

Keywords:

• alzheimer’s disease
• diabetes
• inflammation
• neurodegeneration
• obesity
• receptor

Article highlights.

• RAGE is a multi-ligand receptor of the immunoglobulin superfamily; RAGE is expressed on multiple cell types such as vascular and immune cells, as well as target cells in diabetic complications. The expression of RAGE in most organs is low in homeostasis; a notable example is the lung, in which high levels of RAGE are observed in health.

• Pharmacological modulation of, or genetic deletion of Ager, is protective in aging, in multiple animal models of diabetic complications, in obesity and metabolic dysfunction, in autoimmune and inflammatory settings, in tumors and in models of Alzheimer’s disease.

• The cytoplasmic domain of RAGE binds to the formin DIAPH1. Knockdown of Diaph1 or genetic deletion of Diaph1 blocks RAGE signaling in cell types such as smooth muscle cells, macrophages, microglial cells and transformed cells.

• The critical amino acids in the RAGE cytoplasmic domain have been identified that underlie the interaction between this RAGE domain and the FH1 domain of DIAPH1. Mutation of these amino acids in the RAGE cytoplasmic domain blocks the interaction with DIAPH1 and blocks RAGE ligand-induced signal transduction.

• The finding that mice devoid of Ager are viable and fertile; display protected responses to many forms of infection, sepsis and massive liver injury (resection); and have normal lifespan strongly suggests that blocking RAGE signaling is not likely to cause deleterious side effects. Therefore, targeting the cytoplasmic domain of RAGE–DIAPH1 interaction with small-molecule inhibitors holds great potential to safely block RAGE signaling and prevent the consequences of chronic disease. Definitive testing in human subjects is required.

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Acknowledgements

The authors acknowledge the expert assistance of Ms. Latoya Woods in the preparation of this manuscript.

Declaration of interest

The authors were supported by funding for this work from the National Institutes of Health U.S.A., the Juvenile Diabetes Research Foundation (JDRF) and the American Diabetes Association (ADA). R Ramasamy and AM Schmidt are supported by NIH grants numbers P01HL60901 and 1R24DK103032, and JDRF grant 4-2011-25. AM Schmidt is also supported by NIH grant 1R01HL118565 and ADA grant 1-15-MI-14. A Shekhtman is supported by the NIH grant 1R24DK103032. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the article apart from those disclosed.