RAGE controls activation and anti-inflammatory signalling of protein C

• Published in: PloS one 2014-02, Vol.9 (2), p.e89422-e89422
• Main Authors: Braach, Natascha, Frommhold, David, Buschmann, Kirsten, Pflaum, Johanna, Koch, Lutz, Hudalla, Hannes, Staudacher, Kathrin, Wang, Hongjie, Isermann, Berend, Nawroth, Peter, Poeschl, Johannes
• Format: Article
• Language: English
• Subjects: Activated protein C; Activation; Adhesion; Advanced glycosylation end products; Analysis; Animal models; Animals; Anti-inflammatory agents; Anti-Inflammatory Agents - metabolism; Binding sites; Biochemistry; Biology; Cell adhesion & migration; Cell Adhesion - genetics; Cell migration; Cytokines; Endothelial cells; Endothelial Cells - metabolism; Endothelial Protein C Receptor; Endothelium; Experiments; Glycosylation; Humans; Inflammation; Inflammation - genetics; Inflammation - metabolism; Intercellular adhesion molecule 1; Intercellular Adhesion Molecule-1 - genetics; Intercellular Adhesion Molecule-1 - metabolism; Kinases; Laboratories; Leukocytes; Leukocytes - metabolism; Male; MAP kinase; Mediation; Medicine; Mice; Mice, Inbred C57BL; Mice, Knockout; Microscopy; Mouse devices; mRNA; Muscles; NF-κB protein; Protein C; Protein C - genetics; Protein C - metabolism; Proteins; Receptor for Advanced Glycation End Products; Receptors, Cell Surface - genetics; Receptors, Cell Surface - metabolism; Receptors, Immunologic - genetics; Receptors, Immunologic - metabolism; Recruitment; RNA; Rodents; Signal transduction; Signal Transduction - genetics; Signaling; Thrombomodulin; Thrombomodulin - genetics; Thrombomodulin - metabolism; Trauma; Tumor necrosis factor; Tumor Necrosis Factor-alpha - genetics; Tumor Necrosis Factor-alpha - metabolism; Tumor necrosis factor-α; Up-Regulation - genetics; Vascular cell adhesion molecule 1; Vascular Cell Adhesion Molecule-1 - genetics; Vascular Cell Adhesion Molecule-1 - metabolism
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0089422

The receptor for advanced glycation endproducts, RAGE, is a multiligand receptor and NF-κB activator leading to perpetuation of inflammation. We investigated whether and how RAGE is involved in mediation of anti-inflammatory properties of protein C. We analyzed the effect of protein C on leukocyte adhesion and transmigration in WT- and RAGE-deficient mice using intravital microscopy of cremaster muscle venules during trauma- and TNFα-induced inflammation. Both, protein C (PC, Ceprotin, 100 U/kg) and activated protein C (aPC, 24 µg/kg/h) treatment significantly inhibited leukocyte adhesion in WT mice in these inflammation models. The impaired leukocyte adhesion after trauma-induced inflammation in RAGE knockout mice could not be further reduced by PC and aPC. After TNFα-stimulation, however, aPC but not PC treatment effectively blocked leukocyte adhesion in these mice. Consequently, we asked whether RAGE is involved in PC activation. Since RAGE-deficient mice and endothelial cells showed insufficient PC activation, and since thrombomodulin (TM) and endothelial protein C receptor (EPCR) are reduced on the mRNA and protein level in RAGE deficient endothelial cells, an involvement of RAGE in TM-EPCR-dependent PC activation is likely. Moreover, TNFα-induced activation of MAPK and upregulation of ICAM-1 and VCAM-1 are reduced both in response to aPC treatment and in the absence of RAGE. Thus, there seems to be interplay of the RAGE and the PC pathway in inflammation. RAGE controls anti-inflammatory properties and activation of PC, which might involve EPCR and TM.