S100a6

Cell

Apoptosis proliferation

Figure 3. RAGE-mediated S100 proteins biological functions and transduction pathways. Various members of the S100 proteins family bind to RAGE. S100B activates cell proliferation in a concentration-dependent manner through the formation of reactive oxygen species (ROS) which then activate the Akt (Protein kinase B) and the extracellular signal-regulated kinases (erk) pathways, leading to changes in the activity of NF-kB transcription factor. In contrast, S100A6 induces cellular apoptosis by production of ROS, activation of Erk pathway and changes in NF-kB transcriptional activity but also involves the c-JUN NH2-terminal kinase (JNK). JNK and Erk activation are dependent on ROS formation

Cell

Apoptosis proliferation

Figure 3. RAGE-mediated S100 proteins biological functions and transduction pathways. Various members of the S100 proteins family bind to RAGE. S100B activates cell proliferation in a concentration-dependent manner through the formation of reactive oxygen species (ROS) which then activate the Akt (Protein kinase B) and the extracellular signal-regulated kinases (erk) pathways, leading to changes in the activity of NF-kB transcription factor. In contrast, S100A6 induces cellular apoptosis by production of ROS, activation of Erk pathway and changes in NF-kB transcriptional activity but also involves the c-JUN NH2-terminal kinase (JNK). JNK and Erk activation are dependent on ROS formation although this study did not provide information on the involvement of RAGE in Ap toxicity or on the potential physical competition between the two ligands for the RAGE receptor which could also explain S100B protection (Businaro et al., 2006).

Endogenous secreted soluble RAGE (esRAGE) binds to the diverse RAGE ligands. It could therefore participate to the removal and detoxification of the ligands involved in human diseases by acting as a decoy. The potential use of esRAGE as a therapeutic target was investigated in animal models and results of these studies consistently indicated that administration of esRAGE reduced or limited the development of most RAGE-dependent human disorders. Specifically, esRAGE suppressed Alzheimer's disease-associated pathology and reduced the transport of Ap peptide across the blood-brain barrier in an Alzheimer's disease mouse model (Deane et al., 2003; Lue et al., 2001). In addition, injection of esRAGE in mice blocked the development of tumours and metastasis as well as inflammation and prevented diabetes-associated impaired wound healing (Goova et al., 2001; Hofmann et al., 1999; Taguchi et al., 2000). esRAGE also emerged as a disease marker and clinical studies revealed a specific decrease of circulating esRAGE level in patients with hypertension, Alzheimer's disease or reduced inflammatory response. In contrast, elevated esRAGE level was found in patients with acute lung injury or renal diseases (Geroldi et al., 2006). A second blockade approach of the RAGE-ligand interaction has been investigated in diabetic and Alzheimer's disease mouse models using specific antibodies directed against RAGE and has proven to be successful (Flyvbjerg et al., 2004; Jensen et al., 2006; Lue et al., 2001). However, the use of such approaches needs a perfect understanding of the RAGE-ligand interaction structure as well as the development of antibodies specifically directed against the binding site of a particular ligand on RAGE.

The RAGE-/- and wild type mice present similarly increased immune responses following the induction of delayed-type hypersensitivity (DTH), which generates the production of RAGE ligands like S100 proteins. In contrast, treatment of both wild type and RAGE-/- mice with esRAGE reduces this adaptive immune response (Liliensiek et al., 2004). Similarly, administration of esRAGE to diabetic wild type mice completely restored pain perception, whereas pain perception was only partly restored in diabetic RAGE-/- animals (Bierhaus et al., 2004). These results strongly indicate that RAGE ligands, sequestered by esRAGE, can coactivate receptors other than RAGE which are also involved in these pathological mechanisms. Indeed, it was reported that S100A8/S100A9 bind to heparin sulphate glycosaminoglycans on human HMEC-1 cells devoid of RAGE. Similarly, AGEs can bind to receptors like AGE-R1 and AGE-R2 (He et al., 2000; Robinson et al., 2002; Stitt et al., 1999). Furthermore, Ap peptide can interact with cell surface binding sites such as type A scavenger and a-7 nicotinic acetylcholine receptors (Paresce et al., 1996; Wang et al., 2000b). In addition, RAGE-mediated leukocyte recruitment is dependent on the interaction between RAGE and the p2-integrin Mac-1, and the binding of RAGE to Mac-1 is enhanced by S100 proteins but not by AGEs (Chavakis et al., 2003). The difference in the outcome between different cell types in contact with the same RAGE ligand could also arise from cell-type specific expression of coreceptors. Altogether, this reveals the high complexity of the RAGE network involved in human disease and highly suggests that ligand recognition, RAGE-ligand interaction as well as the biological significance of RAGE activation must be tightly regulated in cells.

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