Receptor for advanced glycation end products (RAGE) regulates sepsis but not the adaptive immune response

Abstract

While the initiation of the adaptive and innate immune response is well understood, less is known about cellular mechanisms propagating inflammation. The receptor for advanced glycation end products (RAGE), a transmembrane receptor of the immunoglobulin superfamily, leads to perpetuated cell activation. Using novel animal models with defective or tissue-specific RAGE expression, we show that in these animal models RAGE does not play a role in the adaptive immune response. However, deletion of RAGE provides protection from the lethal effects of septic shock caused by cecal ligation and puncture. Such protection is reversed by reconstitution of RAGE in endothelial and hematopoietic cells. These results indicate that the innate immune response is controlled by pattern-recognition receptors not only at the initiating steps but also at the phase of perpetuation. IntroductionThe adaptive and the innate immune systems are both capable of initiating inflammation. The two are interconnected at several levels, including the synthesis and action of cytokines, molecules regulating cell-cell interactions, and the activation of transcription factors (1-9). While the molecular events leading to activation of the immune response are well understood, less is known about factors that perpetuate inflammation. One mechanism considered central in the cross-talk between the innate and adaptive immune systems is the redox-dependent activation of the transcription factor NF-κB (1, 4, 9-13). Members of the NF-κB family control the initiation of inflammation by regulating expression of leukocyte adhesion molecules, cytokines, and other factors (10-13), but are also central in terminating inflammation (14)(15)(16)(17)(18). This leaves unanswered the question of the perpetuation of inflammation of the adaptive and innate immune responses.Recently, studies of the receptor for advanced glycation end products (RAGE) (19-23), a member of the immunoglobulin superfamily (23) whose gene is located in the vicinity of the MHC

Multiple levels of regulation determine the role of the receptor for AGE (RAGE) as common soil in inflammation, immune responses and diabetes mellitus and its complications

“…Consistent with this paradigm, blockade of RAGE, either by sRAGE, anti-RAGE F(ab′)2 fragments or the selective expression of dominant negative RAGE in CD4+ T cells, suppressed experimental autoimmune encephalomyelitis (EAE) induced by myelin basic protein peptide and encephalitogenic T cells [75]. When Pasteurella pneumotropica-mediated EAE was induced in Rage −/− mice, they developed typical EAE symptoms and no significant protection was found compared with wild-type mice [12]. In models of delayed type hypersensitivity, Rage −/− mice elicited a normal inflammatory response [12].…”

“…During firm leucocyte arrest, the β 2 -integrins lymphocyte-function-associated-antigen-1 (LFA-1; αLβ ; CD11a/CD18) and MAC-1 are expressed on the leucocyte surface and interact with their endothelial counterreceptors such as intercellular adhesion molecule 1 (ICAM-1) and RAGE. Besides its role as MAC-1 ligand, RAGE-mediated NF-κB activation regulates the gene expression of ICAM-1 and VCAM-1 [12]. In a model of type 2 diabetes, Apoe −/− db/db mice displayed RAGEdependent enhanced production of VCAM-1 and tissue factor and matrix metalloproteinase-9 antigen/activity in aortic tissue, supporting a role of RAGE and its ligands in regulating leucocyte recruitment and adhesion in inflammatory processes.…”

“…Consistent with the proposed central role of RAGE in the immune response, it was demonstrated that RAGE inhibition or deletion protected mice from the lethal effects of septic shock caused by caecal ligation and puncture. Rage −/− mice further displayed reduced NF-κB activation in key target organs of septic shock, as well as a significant reduction of inflammatory cells migrating into the peritoneum [12]. In contrast, injection of exogenous AGE increased lethality and NF-κB activation in RAGE-bearing mice, but not in RAGE-deficient mice [71], further pointing to a causal relationship between RAGE ligands, RAGE signalling, NF-κB activation and lethality in septicaemia.…”

“…When Pasteurella pneumotropica-mediated EAE was induced in Rage −/− mice, they developed typical EAE symptoms and no significant protection was found compared with wild-type mice [12]. In models of delayed type hypersensitivity, Rage −/− mice elicited a normal inflammatory response [12]. Unexpectedly, treatment of Rage −/− mice with sRAGE blocked the inflammatory response to the same extent as in RAGEbearing wild-type mice [12].…”

“…RAGE does not promote the uptake and removal of AGE, but AGE-ligation to RAGE induces inflammation through persistent activation of the proinflammatory transcription factor, nuclear factor kappa-B (NF-κB) [8,9]. When Rage −/− mice were generated [10][11][12] and studied in different pathologies, it became apparent that RAGE is involved in a number of diseases of the innate immune system and RAGE was redefined as a promiscuous pattern recognition receptor (PRR), mediating immune and inflammatory responses, promotion and progression of cancer [13,14], and micro-as well as macrovascular disease [2][3][4][5] by binding a variety of ligands released by inflammatory, stressed and damaged cells [8,15,16]. Subsequently, RAGE×ligand interaction has been associated with survival of RAGE-producing cells, production of cellular reactive oxygen species (ROS), increased levels of phosphorylated extracellular signal-regulated kinase (ERK)1/2, new synthesis of p65 (also known as RelA), NF-κB activation and sustained inflammation [8,15,17,18].…”