The Pattern Recognition Receptor (RAGE) Is a Counterreceptor for Leukocyte Integrins
By T. Chavakis, A. Bierhaus, N. Al‐Fakhri, D. Schneider, S. Witte, T. Linn, M. Nagashima, J. Morser, B. Arnold, K. Preissner and 1 more. Journal of Experimental Medicine, 2003
638 citations recorded by the source corpus.
The pattern recognition receptor, RAGE (receptor for advanced glycation endproducts), propagates cellular dysfunction in several inflammatory disorders and diabetes. Here we show that RAGE functions as an endothelial adhesion receptor promoting leukocyte recruitment. In an animal model of thioglycollate-induced acute peritonitis, leukocyte recruitment was significantly impaired in RAGE-deficient mice as opposed to wild-type mice. In diabetic wild-type mice we observed enhanced leukocyte recruitment to the inflamed peritoneum as compared with nondiabetic wild-type mice; this phenomenon was attributed to RAGE as it was abrogated in the presence of soluble RAGE and was absent in diabetic RAGE-deficient mice. In vitro, RAGE-dependent leukocyte adhesion to endothelial cells was mediated by a direct interaction of RAGE with the β2-integrin Mac-1 and, to a lower extent, with p150,95 but not with LFA-1 or with β1-integrins. The RAGE–Mac-1 interaction was augmented by the proinflammatory RAGE-ligand, S100-protein. These results were corroborated by analysis of cells transfected with different heterodimeric β2-integrins, by using RAGE-transfected cells, and by using purified proteins. The RAGE–Mac-1 interaction defines a novel pathway of leukocyte recruitment relevant in inflammatory disorders associated with increased RAGE expression, such as in diabetes, and could provide the basis for the development of novel therapeutic applications.
Subfields: Clinical Biochemistry, Immunology, Molecular Biology
View Paper: https://www.semanticscholar.org/paper/52c118c44cf35c1025320f7c9a468af858dab5fb
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Citations in the corpus
- Advanced Glycation End Products and Diabetic Complications (2014, background): “RAGE has been identified as receptor for amyloid-beta peptide (Aβ) and β-sheet fibrils [65] S100/calgranulins [66]; amphoterin [67] and Mac-1 [68].”
- Mechanisms of diabetic complications. (2013, background): “This is most likely due to RAGE modulation being upstream of many important pathological pathways relevant to diabetic complications, including ROS generation (122, 636), activation of the immune system (30, 90, 92), release of cytokines (191), and a newly discovered role in glycemic control (78, 12”
- Advanced Glycation End Products and Oxidative Stress in Type 2 Diabetes Mellitus (2015, background): “RAGE belongs to the immunoglobulin superfamily and additionally interacts with a wide range of ligands including S100 calgranulins [54], high mobility group box 1 [55], or Mac-1 [56] which is why RAGE is also classified as a multi-ligand receptor.”
- Advanced glycation end products and RAGE: a common thread in aging, diabetes, neurodegeneration, and inflammation. (2005, background): “RAGE has been identified as receptor for amyloid-beta peptide (Aβ) and β-sheet fibrils (Yan et al., 1996, 2000); S100/calgranulins (Hofmann et al., 1999); amphoterin (Hori et al., 1995; Taguchi et al., 2000); and, most recently, Mac-1 (Chavakis et al., 2003).”
- S100A8 and S100A9 in inflammation and cancer. (2006, background): “functional innate immune responses and chronic inflammation [121,134,135].”
- Advanced glycation end products and vascular inflammation: implications for accelerated atherosclerosis in diabetes. (2004, background): “In diabetic wild-type mice enhanced leukocyte recruitment to the inflamed peritoneum was observed compared with nondiabetic wild-type mice; this phenomenon was abrogated in the presence of soluble RAGE, and was absent in diabetic RAGE-deficient mice [89].”
- Role of advanced glycation end products in cellular signaling (2014, background): “The interaction of RAGE on leukocytes results in activation of sustained NF-κB-dependent gene expression [56].”
- Meta-analyses of genome-wide association studies identify multiple novel loci associated with pulmonary function (2009, background): “In healthy adult mice and humans, AGER is highly expressed in the lung”