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

Liliensiek, Birgit; Weigand, Markus A.; Bierhaus, Angelika; Nicklas, Werner; Kasper, Michael; Hofer, Stefan; Plachky, J.; Gröne, Herman-Josef; Kurschus, Florian C.; Schmidt, Ann Marie; Yan, Shirley ShiDu; Martin, Eike; Schleicher, Erwin; Stern, David M.; Hämmerling, Günter J.; Nawroth, Peter P.; Arnold, Bernd

doi:10.1172/jci18704

Cited by 264 publications

(325 citation statements)

References 61 publications

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“…Rage -/- mice, backcrossed >10 times to a C57Bl/6 background, were generated as described [12] and bred in the animal facility of the Academic Medical Center (Amsterdam, The Netherlands). The Animal Care and Use Committee of the University of Amsterdam approved all experiments.…”

Section: Methodsmentioning

confidence: 99%

“…Several animal studies have shown that RAGE is critically involved in the deleterious effects of acute inflammatory disorders, including sepsis [12,13,14,15,16]. Deletion of the rage gene was initially found to protect against the lethal effects of septic shock in polymicrobial sepsis, which was associated with a strongly reduced activation of NF-κB in the peritoneum and lungs [12].…”

Section: Introductionmentioning

confidence: 99%

“…Deletion of the rage gene was initially found to protect against the lethal effects of septic shock in polymicrobial sepsis, which was associated with a strongly reduced activation of NF-κB in the peritoneum and lungs [12]. Our group previously investigated the role of RAGE in sepsis derived from S. pneumoniae pneumonia [14], showing increased RAGE expression in the lungs upon infection and a relatively protected phenotype of RAGE deficient ( rage -/- ) mice [14].…”

Section: Introductionmentioning

confidence: 99%

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Limited Role of the Receptor for Advanced Glycation End Products during Streptococcus pneumoniae Bacteremia

Achouiti¹,

Vos²,

Beer³

et al. 2013

J Innate Immun

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Streptococcus pneumoniae is one of the most common causes of sepsis. Sepsis is associated with the release of 'damage-associated molecular patterns' (DAMPs). The receptor for advanced glycation end products (RAGE) is a multiligand receptor, abundantly expressed in the lungs, that recognizes several of these DAMPs. Triggering of RAGE leads to activation of the NF-κB pathway and perpetuation of inflammation. Earlier investigations have shown that the absence of RAGE reduces inflammation and bacterial dissemination and increases survival in sepsis caused by S. pneumoniae pneumonia. We hypothesized that the detrimental role of RAGE depends on the level of RAGE expression in the primary organ of infection. By directly injecting S. pneumoniae intravenously, thereby circumventing the extensive RAGE-expressing lung, we here determined whether RAGE contributes to an adverse outcome of bacteremia or whether its role is restricted to primary lung infection. During late-stage infection (48 h), rage^-/- mice had an attenuated systemic inflammatory response, as reflected by lower plasma levels of proinflammatory cytokines, reduced endothelial cell activation (as measured by E-selectin levels) and less neutrophil accumulation in lung tissue. However, RAGE deficiency did not influence bacterial loads or survival in this model. In accordance, plasma markers for cell injury were similar in both mouse strains. These results demonstrate that while RAGE plays a harmful part in S. pneumoniae sepsis originating from the respiratory tract, this receptor has a limited role in the outcome of primary bloodstream infection by this pathogen.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Limited Role of the Receptor for Advanced Glycation End Products during Streptococcus pneumoniae Bacteremia

Achouiti¹,

Vos²,

Beer³

et al. 2013

J Innate Immun

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“…However, in the late and progressive stages of AD dysfunction, depletion of the enzyme's chief and essential cofactor, glutathione, reduces overall activity of the GLO1-AGE detoxifying system, thus facilitating increased AGE production and accumulation [65,66]. Altogether, these findings underscore a potentially profound link between peripheral and central inflammation, which prompts the question: to what extent might anti-AGE/RAGE therapies provide protective measures for neurodegeneration and AD, given the prominence of cellular stress driven by increased RAGE ligand burden [67][68][69].…”

Section: Consequences Of Rage Signal Transductionmentioning

confidence: 99%

“…However, controversy arose after a report that Ager deficient mice with EAE displayed no differences in disease severity [67].…”

Section: Rage Snps Animal Findings Human Findingsmentioning

confidence: 99%

The Receptor for Advanced Glycation Endproducts (RAGE) and Mediation of Inflammatory Neurodegeneration

Derk

MacLean

Juranek

et al. 2018

J Alzheimers Dis Parkinsonism

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Soluble receptor for advanced glycation end products triggers a proinflammatory cytokine cascade via β2 integrin Mac‐1

Pullerits¹,

Brisslert²,

Jonsson³

et al. 2006

Arthritis & Rheumatism

109

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Objective. Receptor for advanced glycation end products (RAGE) is a cell surface molecule that binds a variety of ligands, including high mobility group box chromosomal protein 1 (HMGB-1), a potent proinflammatory cytokine. RAGE-ligand interaction leads to an inflammatory response. A truncated form of the receptor, soluble RAGE (sRAGE), has been suggested to function as a decoy abrogating cellular activation, but its endogenous activity is not fully understood. We undertook this study to assess the properties of sRAGE in vivo and in vitro and to analyze the role of sRAGE in HMGB-1-induced arthritis.Methods. Mice were injected intraarticularly with HMGB-1 and treated systemically with sRAGE prior to histologic joint evaluation. All animals were subjected to peritoneal lavage to assess the local effect of sRAGE treatment. For in vitro studies, mouse splenocytes were incubated with sRAGE followed by assessment of NF-B activation and cytokine production. The chemotactic properties of sRAGE were investigated using in vitro migration assay.Results. Soluble RAGE was determined to have proinflammatory properties since it gave rise to production of interleukin-6, tumor necrosis factor ␣, and macrophage inflammatory protein 2. This effect was triggered by interaction with leukocyte ␤2 integrin Mac-1 and was mediated via NF-B. Systemic treatment with sRAGE significantly down-regulated HMGB-1-triggered arthritis, but the observed effect was due to a deviation of the inflammatory response from the joint to the peritoneal cavity rather than a genuine antiinflammatory effect. Apart from its proinflammatory properties, sRAGE was proven to act as a chemotactic stimulus for neutrophils. Conclusion. We conclude that sRAGE interacts with Mac-1, thereby acting as an important proinflammatory and chemotactic molecule.The receptor for advanced glycation end products (RAGE) is a multiligand member of the immunoglobulin superfamily, being expressed as a cell surface molecule and playing a key role in diverse inflammatory processes (1). RAGE was first described as a receptor for "advanced glycation end products" (AGEs), the products of nonenzymatic glycation and oxidation of proteins and lipids that accumulate in the setting of diabetes (2). The receptor protein is composed of 3 immunoglobulin-like regions, a transmembrane domain, and a highly charged short cytosolic tail that is essential for intracellular signaling. The V domain in the extracellular part of the receptor protein is critical for ligand binding and interacts with a diverse class of ligands due to its ability to recognize 3-dimensional structures rather than specific amino acid sequences (3). Studies have shown that engagement of RAGE by its ligands results in a rapid and sustained cellular activation. Sustained receptor engagement leads to a positive feedback loop in which ligand-receptor interaction increases expression of the receptor itself on the cell surface (3). However, in normal tissues, RAGE is expressed at low levels (4).Soluble RAGE (sRAGE), a truncated form of...

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

Cited by 264 publications

References 61 publications

Limited Role of the Receptor for Advanced Glycation End Products during <b><i>Streptococcus pneumoniae</i></b> Bacteremia

Limited Role of the Receptor for Advanced Glycation End Products during <b><i>Streptococcus pneumoniae</i></b> Bacteremia

The Receptor for Advanced Glycation Endproducts (RAGE) and Mediation of Inflammatory Neurodegeneration

Soluble receptor for advanced glycation end products triggers a proinflammatory cytokine cascade via β2 integrin Mac‐1

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