RAGE is a cell surface nucleic acid sensor — ASN Events
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  3. RAGE is a cell surface nucleic acid sensor

RAGE is a cell surface nucleic acid sensor (#9)

Damien Bertheloot 1 , Cherilyn M Sirois 2 , Allison L Miller 3 , Tengchuan Jin 4 , Natalio Garbi 5 , T. Sam Xiao 4 , Eicke Latz 1 6 7
  1. Institute of Innate Immunity, University of Bonn, Bonn, NRW, Germany
  2. Center for Translational Research, College of Health Sciences, Universidad de las Américas, Quito, Ecuador
  3. Division of Respiratory Inflammation & Autoimmunity, MedImmune LLC, Gaithersburg, MD, USA
  4. Structural Immunobiology Unit, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
  5. Institutes of Molecular Medicine and Experimental Immunology, University of Bonn, Bonn, NRW, Germany
  6. Department of Medicine, Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA, USA
  7. German Center for Neurodegenerative Diseases, University of Bonn, Bonn, NRW, Germany

RAGE is a multi-ligand cell surface receptor of the Immunoglobulin super-family. It is composed of three extracellular immunoglobulin-like domains (V, C1 and C2), a single trans-membrane domain and a short cytoplasmic domain. RAGE is predominately expressed in the lung under normal conditions. However, during inflammation, RAGE expression increases dramatically in tissues like the vascular system, CNS and some hematopoietic cells. RAGE ligands are structurally heterogeneous and bind to RAGE through sequence nonspecific electrostatic interactions. They include advanced glycation end products, the DNA binding protein HMGB1, several proteins of the S100 family and certain types of β-sheet fibrils such as β-amyloid. Hence, RAGE is involved in many chronic inflammatory diseases such as diabetes, Alzheimer’s disease, asthma and systemic lupus erythematosus.

Using EMSA and AlphaScreen, we showed that DNA and RNA bind to RAGE in a sequence nonspecific manner through electrostatic interaction of their phosphate backbone with the V and C1 domains. Human embryonic kidney (HEK) cells expressing RAGE bound more fluorescently labelled RNA and DNA than non-expressing cells as shown by microscopy and flow cytometry. In order to investigate the effect of RAGE expression on nucleic acid (NA) sensing by endosomal TLRs, we used HEK cells expressing TLR7, TLR8, TLR13 (ssRNA) or TLR9 (DNA) together with RAGE and found that RAGE increased NA induced activation of the transcription factor NFκB.  Finally, in a mouse model of acute lung inflammation, DNA inhalation induced a strong inflammatory response in WT mice, while RAGE knockout mice displayed dramatically reduced inflammation.

We show that RAGE binds NAs at the cell surface, increases their uptake and thereby amplifies the activation of endosomal TLRs. This work helps to further elucidate the function of RAGE in the development and perpetuation of chronic inflammation and presents RAGE as a promising target in the development of anti-inflammatory treatments.