RAGE Controls Activation and Anti-Inflammatory Signalling of Protein C

Abstract

AimsThe 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.Methods and ResultsWe 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.ConclusionRAGE controls anti-inflammatory properties and activation of PC, which might involve EPCR and TM.

Relationships Among Circulating Levels of Hemostasis Inhibitors, Chemokines, Adhesion Molecules, and MRI Characteristics in Multiple Sclerosis

“…Several differences between MS patients and HI in PC correlation with sICAM1, sNCAM, and sVAP1 concentrations support dysregulation, associated with the MS disease, of the adhesion molecules and PC pathways. The absence of correlation between PC and sICAM and sNCAM in MS patients could be reflected in a decreased inhibition of leukocyte adhesion and transmigration (7,8).…”

“…Among hemostasis components, PC has coagulation inhibitor activity and also anti-inflammatory and cell protective properties (6). Activated PC might inhibit leukocyte adhesion and transmigration, downregulating endothelial expression of intercellular adhesion molecule-1 (ICAM1) and vascular cell adhesion molecule-1 (VCAM1) (7,8). In MS-related vascular changes, circulating soluble (s) forms of cell adhesion molecules (CAMs) can result from activated membranes shedding in response to endothelial damage (9).…”

Pulmonary receptor for advanced glycation end-products promotes asthma pathogenesis through IL-33 and accumulation of group 2 innate lymphoid cells

“…Previous work by our lab has shown that pulmonary RAGE levels do not change in mice challenged with allergen (20). RAGE activation, however, is thought to induce NF-κB nuclear translocation and amplification of downstream signaling pathways (65, 66), including a number of which promote expression of adhesion molecules such as VCAM-1 (67) and ICAM-1 (68). Two studies exploring the relationship between RAGE and ICAM-1 expression on endothelial cells demonstrated complementary roles for ICAM-1 and RAGE in mediating leukocyte adhesion to endothelium (69, 70).…”

LXR agonist T0901317 upregulates thrombomodulin expression in glomerular endothelial cells by inhibition of nuclear factor-κB

“…Previous studies suggest that LXR activation may enhance TM activity via the TM-thrombin-PC system. Activated TM simultaneously binds to thrombin and PC to form a complex on the surface of endothelial cells, which expresses the endothelial cell PC receptor (EPCR) (31)(32)(33). APC binds with EPCR to downregulate the production of inflammatory cytokines (34).…”