Herold, K. et al. Receptor for advanced glycation end products (RAGE) in a dash to the rescue: inflammatory signals gone awry in the primal response to stress. J. Leukoc. Biol. 82, 204-212

Department of Surgery, Columbia University, New York, New York, United States
Journal of Leukocyte Biology (Impact Factor: 4.29). 09/2007; 82(2):204-12. DOI: 10.1189/jlb.1206751
Source: PubMed


The multiligand receptor for advanced glycation end products (RAGE) of the Ig superfamily transduces the biological impact of discrete families of ligands, including advanced glycation end products, certain members of the S100/calgranulin family, high mobility group box-1, Mac-1 (alpha(M)beta(2), CD11b/CD18), and amyloid-beta peptide and beta-sheet fibrils. Although structurally dissimilar, at least at the monomeric level, recent evidence suggests that oligomeric forms of these RAGE ligands may be especially apt to activate the receptor and up-regulate a program of inflammatory and tissue injury-provoking genes. The challenge in probing the biology of RAGE and its impact in acute responses to stress and the potential development of chronic disease is to draw the line between mechanisms that evoke repair versus those that sustain inflammation and tissue damage. In this review, we suggest the concept that the ligands of RAGE comprise a primal program in the acute response to stress. When up-regulated in environments laden with oxidative stress, inflammation, innate aging, or high glucose, as examples, the function of these ligand families may be transformed from ones linked to rapid repair to those that drive chronic disease. Identification of the threshold beyond which ligands of RAGE mediate repair versus injury is a central component in delineating optimal strategies to target RAGE in the clinic.

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    • "Experimental pulmonary inoculation with C. neoformans strain H99c results in the recruitment of TLR4 + and RAGE + macrophages and DCs to the lungs during infection TLR4 and RAGE have been identified as receptors for S100A8/A9 and SAA3 (Ehrchen et al., 2009; Foell et al., 2007; Herold et al., 2007). Thus, we determined the expression of TLR4 and RAGE on the surface of pulmonary macrophages and DCs derived from mice inoculated with WT C. neoformans strain H99 or C. neoformans strain H99c on days 5 and 7 post-inoculation, the time points at which production of antimicrobial peptides and acute phase proteins, respectively, was highest in mice inoculated with C. neoformans strain H99c. "
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    ABSTRACT: Cryptococcus neoformans is a significant cause of fungal meningitis in patients with impaired T cell-mediated immunity (CMI). Experimental pulmonary infection with a C. neoformans strain engineered to produce interferon-gamma, H99γ, results in the induction of Th1-type CMI, resolution of the acute infection, and protection against challenge with wild type (WT) Cryptococcus. Considering that individuals with suppressed T CMI are highly susceptible to pulmonary C. neoformans infection, we sought to determine whether or not antimicrobial peptides were produced in mice inoculated with H99γ. Thus, we measured the levels of antimicrobial peptides Lipocalin-2, S100A8, S100A9, calprotectin (S100A8/A9 heterodimer), serum amyloid A-3 (SAA3), and their putative receptors TLR4 and the receptor for advanced glycation end products [RAGE] in mice during primary and recall responses against C. neoformans infection. Results showed increased levels of IL-17A and IL-22, cytokines known to modulate antimicrobial peptide production. We also observed increased levels of Lipocalin-2, S100A8, S100A9, and SAA3 as well as TLR4+ and RAGE+ macrophages and dendritic cells in mice inoculated with H99γ compared to WT H99. Similar results were observed in the lungs of H99γ-immunized, compared to heat-killed C. neoformans-immunized, mice following challenge with WT yeast. However, IL-22 deficient mice inoculated with H99γ demonstrated antimicrobial peptide production and no change in survival rates compared to WT mice. These studies demonstrate that protection against cryptococcosis is associated with increased production of antimicrobial peptides in the lungs of protected mice that are not solely in response to IL-17A and IL-22 production and may be coincidental rather than functional.
    Full-text · Article · Apr 2014 · Microbiology
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    • "RAGE is also a receptor for Damaged-Associated Molecular Pattern molecules that originate from damaged cells and alert the immune system to tissue trauma [3]. In particular, RAGE interacts with high mobility group box 1 (HMGB1), the prototypical DAMP, and S100 proteins [4]. How RAGE can interact with a diverse variety of molecules has been discussed by one of us in a recent review [5]. "
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    ABSTRACT: The human receptor for advanced glycation endproducts (RAGE) is a multiligand cell surface protein belonging to the immunoglobulin superfamily, and is involved in inflammatory and immune responses. Most importantly, RAGE is considered a receptor for HMGB1 and several S100 proteins, which are Damage-Associated Molecular Pattern molecules (DAMPs) released during tissue damage. In this study we show that the Ager gene coding for RAGE first appeared in mammals, and is closely related to other genes coding for cell adhesion molecules (CAMs) such as ALCAM, BCAM and MCAM that appeared earlier during metazoan evolution. RAGE is expressed at very low levels in most cells, but when expressed at high levels, it mediates cell adhesion to extracellular matrix components and to other cells through homophilic interactions. Our results suggest that RAGE evolved from a family of CAMs, and might still act as an adhesion molecule, in particular in the lung where it is highly expressed or under pathological conditions characterized by an increase of its protein levels.
    Full-text · Article · Jan 2014 · PLoS ONE
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    • "Triggering TLR2 and TLR4 signaling pathways leads to the activation of nuclear factor κB (NF-κB), through the accessory protein MyD88, and the subsequent regulation of immune and inflammatory genes, including inflammatory cytokines such as tumor necrosis factor α (TNFα), with the activation of mitogen-activated protein kinases [11-13]. Receptor for advanced glycation end products (RAGE) is a multi-ligand receptor that belongs to the immunoglobulin superfamily [14]. Other known RAGE ligands include amyloid [15] and S100 [16]. "
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    ABSTRACT: High-mobility group box 1 (HMGB1) was initially discovered as a nuclear protein that interacts with DNA as a chromatin-associated non-histone protein to stabilize nucleosomes and to regulate the transcription of many genes in the nucleus. Once leaked or actively secreted into the extracellular environment, HMGB1 activates inflammatory pathways by stimulating multiple receptors, including Toll-like receptor (TLR) 2, TLR4, and receptor for advanced glycation end products (RAGE), leading to tissue injury. Although HMGB1's ability to induce inflammation has been well documented, no studies have examined the role of HMGB1 in wound healing in the gastrointestinal field. The aim of this study was to evaluate the role of HMGB1 and its receptors in the healing of gastric ulcers. We also investigated which receptor among TLR2, TLR4, or RAGE mediates HMGB1's effects on ulcer healing. Gastric ulcers were induced by serosal application of acetic acid in mice, and gastric tissues were processed for further evaluation. The induction of ulcer increased the immunohistochemical staining of cytoplasmic HMGB1 and elevated serum HMGB1 levels. Ulcer size, myeloperoxidase (MPO) activity, and the expression of tumor necrosis factor α (TNFα) mRNA peaked on day 4. Intraperitoneal administration of HMGB1 delayed ulcer healing and elevated MPO activity and TNFα expression. In contrast, administration of anti-HMGB1 antibody promoted ulcer healing and reduced MPO activity and TNFα expression. TLR4 and RAGE deficiency enhanced ulcer healing and reduced the level of TNFα, whereas ulcer healing in TLR2 knockout (KO) mice was similar to that in wild-type mice. In TLR4 KO and RAGE KO mice, exogenous HMGB1 did not affect ulcer healing and TNFα expression. Thus, we showed that HMGB1 is a complicating factor in the gastric ulcer healing process, which acts through TLR4 and RAGE to induce excessive inflammatory responses.
    Full-text · Article · Nov 2013 · PLoS ONE
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