The receptor for advanced glycation end products (RAGE) is a non-specific multi-ligand pattern recognition receptor capable of binding to a range of structurally diverse ligands, expressed on a ...variety of cell types, and performing different functions. The ligand-RAGE axis can trigger a range of signaling events that are associated with diabetes and its complications, neurological disorders, cancer, inflammation and other diseases. Since RAGE is involved in the pathophysiological processes of many diseases, targeting RAGE may be an effective strategy to block RAGE signaling.
Damage-associated molecular pattern (DAMP) molecules have been introduced as important proinflammatory factors of innate immunity. One example known for many years to be expressed in cells of myeloid ...origin are phagocytic S100 proteins, which mediate inflammatory responses and recruit inflammatory cells to sites of tissue damage. An emerging concept of pattern recognition involves the multiligand receptor for advanced glycation end products (RAGE) and Toll-like receptors (TLRs) in sensing not only pathogen-associated molecular patterns (PAMPs) but also endogenous DAMPs, including S100 proteins. S100A8, S100A9, and S100A12 are found at high concentrations in inflamed tissue, where neutrophils and monocytes belong to the most abundant cell types. They exhibit proinflammatory effects in vitro at concentrations found at sites of inflammation in vivo. Although S100A12 binds to RAGE, at least part of the proinflammatory effects of the S100A8/S100A9 complex depend upon interaction with other receptors. Because of the divergent expression patterns, the absence of S100A12 in rodents, the different interaction partners described, and the specific intracellular and extracellular effects reported for these proteins, it is important to differentiate between distinct S100 proteins rather than subsuming them with the term "S100/calgranulins." Analyzing the molecular basis of the specific effects exhibited by these proteins in greater detail bears the potential to elucidate important mechanisms of innate immunity, to establish valid biomarkers of phagocytic inflammation, and eventually to reveal novel targets for innovative anti-inflammatory therapies.
ABSTRACT
Soluble receptor for advanced glycation end products (sRAGE), shed from cell surfaces, is found in human circulation and has been implicated in cardiovascular disease. Its pathophysiological ...regulation and underlying mechanisms are scarcely understood. In endothelium‐specific human RAGE transgenic mice, human sRAGE was detected in circulation, whereas its level was markedly increased after LPS treatment. That increase was preceded by a rapid rise in TNF‐α level. Treatment with TNF‐α also significantly increased serum sRAGE. In human microvascular endothelial cells or human umbilical vein endothelial cells with RAGE overexpression, TNF‐α markedly induced RAGE shedding, which was dependent on MMP9 and ADAM10. TNF‐α–stimulated MMP9 expression was completely dependent on JNK activation, with its inhibition partially effective in suppressing TNF‐α–induced RAGE shedding. In contrast, TNF‐α transiently induced activation transcription factor (ATF)4, a major component in unfolded protein response (UPR), whereas knockdown of ATF4 abrogated TNF‐α–stimulated RAGE shedding. Protein levels of the pro and activated forms of ADAM10 were also decreased by ATF4 knockdown, whereas inhibition of other components of UPR, including XBP1 and ATF6, failed to block TNF‐α–stimulated RAGE shedding. Although the endoplasmic reticulum stressors thapsigargin and tunicamycin induced markedly and sustained expression of ATF4 and XBP‐1, they did not induce RAGE shedding to the same level as TNF‐α, suggesting that ATF4 is necessary but not sufficient alone for TNF‐α–mediated RAGE shedding. ATF4 inhibition did not affect TNF‐α–stimulated MMP9 expression, whereas inhibition of JNK activity did not influence ADAM10 activation. Thus, inflammatory cascades including TNF‐α induced RAGE shedding in endothelial cells in vivo and in vitro. JNK and ATF4 may be 2 platforms for regulation of TNF‐α–stimulated RAGE shedding.—Miyoshi, A., Koyama, S., Sasagawa‐Monden, M., Kadoya, M., Konishi, K., Shoji, T., Inaba, M., Yamamoto, Y., Koyama, H. JNK and ATF4 as two important platforms for tumor necrosis factor‐α–stimulated shedding of receptor for advanced glycation end products. FASEB J. 33, 3575–3589 (2019). www.fasebj.org
Current studies have shown that long-term exposure to fine particulate matter (PM
) can aggravate lung injury in asthmatic children. The HMGB1/RAGE pathway may play an important role, but few studies ...on the HMGB1/RAGE signaling pathway in PM
-induced asthma have been performed. Epigallocatechin-3-gallate (EGCG), which has antioxidant, anti-inflammatory and immunomodulatory effects, has not been examined in studies at home and abroad. In this study, we established an animal model of asthma and observed that the lung tissue was damaged, inflammatory cells infiltrated, bronchial wall thickness (WTt) and bronchial smooth muscle thickness (WTm) increased and the HMGB1 and RAGE mRNA and protein expression increased. The asthmatic rats exposed to PM
showed significantly increased lung injury and inflammatory cell infiltration, WTt and WTm further increased, and HMGB1 and RAGE mRNA and protein levels were higher than those in the asthma group. The asthmatic rats exposed to PM
were treated with EGCG, which alleviated the lung injury, reduced the number of inflammatory cells, decreased WTt and WTm, and reduced the expression of HMGB1 and RAGE mRNA and protein. The high-dose group showed more significant effects than the other groups. In conclusion, our results suggest that HMGB1 and RAGE are involved in the pathogenesis of asthma. PM
exposure significantly aggravated airway inflammation injury in asthmatic rats. EGCG can reduce lung injury and airway remodeling in PM
-exposed asthmatic rats and has lung protective effects. The mechanism may be related to regulation of the HMGB1/RAGE signaling pathway. Our results may provide new ideas and methods for the prevention and treatment of PM
-induced asthma.
Numerous hypotheses including amyloid cascade, cholinergic, and oxidative have been proposed for pathogenesis of Alzheimer’s disease (AD). The data suggest that advanced glycation end products (AGEs) ...and its receptor RAGE (receptor for AGE) are involved in the pathogenesis of AD. AGE–RAGE stress, defined as a balance between stressors (AGE, RAGE) and anti-stressors (sRAGE, AGE degraders) in favor of stressors, has been implicated in pathogenesis of diseases. AGE and its interaction with RAGE-mediated increase in the reactive oxygen species (ROS) damage brain because of its increased vulnerability to ROS. AGE and ROS increase the synthesis of amyloid β (Aβ) leading to deposition of Aβ and phosphorylation of tau, culminating in formation of plaques and neurofibrillary tangles. ROS increase the synthesis of Aβ, high-mobility group box 1(HMGB1), and S100 that interacts with RAGE to produce additional ROS resulting in enhancement of AD pathology. Elevation of ROS precedes the Aβ plaques formation. Because of involvement of AGE and RAGE in AD pathology, the treatment should be targeted at lowering AGE levels through reduction in consumption and formation of AGE, and lowering expression of RAGE, blocking of RAGE ligand binding, increasing levels of soluble RAGE (sRAGE), and use of antioxidants. The above treatment aspect of AD is lacking. In conclusion, AGE–RAGE stress initiates, and Aβ, HMGB1, and S100 enhance the progression of AD. Reduction of levels of AGE and RAGE, elevation of sRAGE, and antioxidants would be beneficial therapeutic modalities in the prevention, regression, and slowing of progression of AD.
Although there is debate about the estimated health burden of rabies, the estimates of direct mortality and the DALYs due to rabies are among the highest of the neglected tropical diseases. Poor ...surveillance, underreporting in many developing countries, frequent misdiagnosis of rabies, and an absence of coordination among all the sectors involved are likely to lead to underestimation of the scale of the disease It is clear, however, that rabies disproportionately affects poor rural communities, and particularly children. Most of the expenditure for postexposure prophylaxis is borne by those who can least afford it. As a result of growing dog and human populations, the burden of human deaths from rabies and the economic costs will continue to escalate in the absence of concerted efforts and investment for control. Since the first WHO Expert Consultation on Rabies in 2004, WHO and its network of collaborating centres on rabies, specialized national institutions, members of the WHO Expert Advisory Panel on Rabies and partners such as the Gates Foundation, the Global Alliance for Rabies Control and the Partnership for Rabies Prevention, have been advocating the feasibility of rabies elimination regionally and globally and promoting research into sustainable cost-effective strategies. Those joint efforts have begun to break the cycle of rabies neglect, and rabies is becoming recognized as a priority for investment. This Consultation concluded that human dog-transmitted rabies is readily amenable to control, regional elimination in the medium- term and even global elimination in the long-term. A resolution on major neglected tropical diseases, including rabies, prepared for submission to the World Health Assembly in May 2013 aims at securing Member States' commitment to the control, elimination or eradication of these diseases. Endorsement of the resolution would open the door for exciting advances in rabies prevention and control.
Brain aging is characterized by several structural, biochemical and molecular changes which can vary among different individuals and can be influenced by genetic, environmental and lifestyle factors. ...Accumulation of protein aggregates, altered neurotransmitter composition, low-grade chronic inflammation and prolonged oxidative stress have been shown to contribute to brain tissue damage. Among key metabolic byproducts, advanced glycation end products (AGEs), formed endogenously through non-enzymatic reactions or acquired directly from the diet or other exogenous sources, have been detected to accumulate in brain tissue, exerting detrimental effects on cellular structure and function, contributing to neurodegeneration and cognitive decline. Upon binding to signal transduction receptor RAGE, AGEs can initiate pro-inflammatory pathways, exacerbate oxidative stress and neuroinflammation, thus impairing neuronal function and cognition. AGE-RAGE signaling induces programmed cell death, disrupts the blood-brain barrier and promotes protein aggregation, further compromising brain health. In this review, we investigate the intricate relationship between the AGE-RAGE pathway and brain aging in order to detect affected molecules and potential targets for intervention. Reduction of AGE deposition in brain tissue either through novel pharmacological therapeutics, dietary modifications, and lifestyle changes, shows a great promise in mitigating cognitive decline associated with brain aging.
•Brain aging can be mediated by chronic inflammation and prolonged oxidative stress.•AGEs accumulate in brain tissue, exerting detrimental effects on cellular function.•RAGE initiates pro-inflammatory pathways, oxidative stress and neuroinflammation.•AGE-RAGE signaling disrupts BBB, promotes protein aggregation and induces apoptosis.•Dietary, lifestyle changes and pharmacological interventions can mitigate cognitive decline.
In this research, we examine customer rage-associated emotions, expressions, and behaviors following service failure. Three independent studies involving 656 respondents and multiple methods are ...employed to investigate customer rage. Scales for each form of rage emotion, expression, and behavior were developed and used to assess their interrelationships. Results suggest that different forms of customer rage emotions tend to be linked to different types of expressions and behaviors. For example, both Rancorous Rage and Retaliatory Rage emotions tend to increase Verbal expressions (such as raising one's voice, yelling, and making insulting remarks). In contrast, Retaliatory Rage emotion increases Physical expressions (tried to physically harm a service employee, tried to cause damage to property, and threatened to damage property) and Displaced expressions (took anger out on other people nearby, yelled at other people, and took their anger out on other people later on) whereas Rancorous Rage emotion decreases Physical and Displaced expressions. Interestingly, Verbal expressions are linked to passive-aggressive behaviors, such as switching service providers and spreading negative word of mouth while Physical expressions are linked to relatively aggressive behavior, such as a desire for revenge. Implications for scholarly research and retailers are discussed.
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