Pattern recognition receptors mediate pro-inflammatory effects of extracellular mitochondrial transcription factor A (TFAM)

Schindler, Stephanie M.; Frank, Marion E.; Annis, Jessica L.; Maier, Steven F.; Klegeris, Andis

doi:10.1016/j.mcn.2018.04.005

Cited by 34 publications

(25 citation statements)

References 54 publications

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“…16 Splenocytes can also respond to mitochondrial DNA in a RAGE-dependent fashion, although it is unclear if Mitochondrial Transcription Factor A (TFAM) binding to RAGE might be mediating some or all of this response as this protein is associated with the isolated DNA. 17 In the absence of direct binding studies, ligand binding can be inferred by functional analyses where targeting RAGE brings about a phenotypic difference. These types of studies have provided indirect identification of numerous potential RAGE ligands.…”

Section: Rage Ligandsmentioning

confidence: 99%

“…Using an inducible expression system for RAGE, labeled oligodeoxynucleotides bound to HEK293T cells in a RAGE‐dependent manner 16 . Splenocytes can also respond to mitochondrial DNA in a RAGE‐dependent fashion, although it is unclear if Mitochondrial Transcription Factor A (TFAM) binding to RAGE might be mediating some or all of this response as this protein is associated with the isolated DNA 17 …”

Section: Introductionmentioning

confidence: 99%

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The role of RAGE in host pathology and crosstalk between RAGE and TLR4 in innate immune signal transduction pathways

2020

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Although the innate immune receptor protein, Receptor for Advanced Glycation End products (RAGE), has been extensively studied, there has been renewed interest in RAGE for its potential role in sepsis, along with a host of other inflammatory diseases of chronic, noninfectious origin. In contrast to other innate immune receptors, for example, Toll-like receptors (TLRs), that recognize ligands derived from pathogenic organisms that are collectively known as "pathogen-associated molecular patterns" (PAMPs) or host-derived "damage-associated molecular patterns" (DAMPs), RAGE has been shown to recognize a broad collection of DAMPs exclusively. Historically, these DAMPs have been shown to be pro-inflammatory in nature. Early studies indicated that the adaptor molecule, MyD88, might be important for this change. More recent studies have explored further the mechanisms underlying this inflammatory change. Overall, the newer results have shown that there is extensive crosstalk between RAGE and TLRs. The three canonical RAGE ligands, Advanced Glycation End products (AGEs), HMGB1, and S100 proteins, have all been shown to activate both TLRs and RAGE to varying degrees in order to induce inflammation in in vitro models. As with any field that delves deeply into innate signaling, obstacles of reagent purity may be a cause of some of the discrepancies in the literature, and we have found that commercial antibodies that have been widely used exhibit a high degree of nonspecificity. Nonetheless, the weight of published evidence has led us to speculate that RAGE may be physically interacting with TLRs on the cell surface to elicit inflammation via MyD88-dependent signaling.

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Section: Rage Ligandsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The role of RAGE in host pathology and crosstalk between RAGE and TLR4 in innate immune signal transduction pathways

2020

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“…TFAM upregulates secretion of IL-6 and cytotoxins in primary microglia that were obtained from post-mortem human samples or THP-1 human monocytic cells, a model of human microglia (102). Administration of TFAM into the cisterna magna in the rodent model increases levels of pro-inflammatory cytokines, including IL-1, IL-6, and TNF-, in the hippocampus and frontal cortex (103), which are the predominant regions affected by AD (89). These results underscore the ability of extracellular TFAM to induce pro-inflammatory responses in microglia.…”

Section: Mitochondrial-inflammation Axis In Ad Pathology Evidence Formentioning

confidence: 99%

“…Furthermore, when combined with CpG-rich mtDNA, TFAM can activate RAGE to mediate a pro-inflammatory immune response and promote the production of TNF- via the PI3K/AKT and ERK pathways (104). Accordingly, blocking RAGE with antagonistic antibodies inhibits the secretion of monocyte chemotactic protein-1 (MCP-1) in TFAM-stimulated THP-1 cells (103). Considering that RAGE binds to A (105,106) and that microglia express high levels of RAGE in patients with AD (107), the TFAM-RAGE pathway may potentially play a role in AD pathogenesis (87).…”

Section: Mitochondrial-inflammation Axis In Ad Pathology Evidence Formentioning

confidence: 99%

Emerging perspectives on mitochondrial dysfunction and inflammation in Alzheimer’s disease

et al. 2020

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Despite enduring diverse insults, mitochondria maintain normal functions through mitochondrial quality control. However, the failure of mitochondrial quality control resulting from excess damage and mechanical defects causes mitochondrial dysfunction, leading to various human diseases. Recent studies have reported that mitochondrial defects are found in Alzheimer's disease (AD) and worsen AD symptoms. In AD pathogenesis, mitochondrial dysfunction-driven generation of reactive oxygen species (ROS) and their contribution to neuronal damage has been widely studied. In contrast, studies on mitochondrial dysfunction-associated inflammatory responses have been relatively scarce. Moreover, ROS produced upon failure of mitochondrial quality control may be linked to the inflammatory response and influence the progression of AD. Thus, this review will focus on inflammatory pathways that are associated with and initiated through defective mitochondria and will summarize recent progress on the role of mitochondria-mediated inflammation in AD. We will also discuss how reducing mitochondrial dysfunction-mediated inflammation could affect AD. [BMB Reports 2020; 53(1): 35-46]

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“…Neuroprotection by AMPK observed in some of the in vivo disease/injury models may block microglial proinflammatory activation, which can be triggered by receiving danger signals from damaged neurons (Roh and Sohn, 2018; Venegas and Heneka, 2017; Schindler et al, 2018). Therefore, the AMPK‐induced microglial shift to the anti–inflammatory phenotype may be caused not only by the direct effects of AMPK on microglia described in the previous section but also by the neuroprotective effects of AMPK.…”

Section: Ampk and Neurodegenerationmentioning

confidence: 99%

Involvement of AMP‐activated protein kinase in neuroinflammation and neurodegeneration in the adult and developing brain

Saito

Shimada

Das

2019

Intl J of Devlp Neuroscience

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Microglial activation followed by neuroinflammation is a defense mechanism of the brain to eliminate harmful endogenous and exogenous materials including pathogens and damaged tissues, while excessive or chronic neuroinflammation may cause or exacerbate neurodegeneration observed in brain injuries and neurodegenerative diseases. Depending on conditions/environments during activation, microglia acquire distinct phenotypes, such as pro‐inflammatory, anti‐inflammatory, and disease‐associated phenotypes, and show their ability to phagocytose various objects and produce pro‐and anti‐inflammatory mediators. Prevention of excessive inflammation by regulating the microglia's pro/anti‐inflammatory balance is important for alleviating progression of brain injuries and diseases. Among many factors involved in the regulation of microglial phenotypes, cellular energy status plays an important role. Adenosine monophosphate‐activated protein kinase (AMPK), which serves as a master sensor and regulator of energy balance, is considered a candidate molecule. Accumulating evidence from adult rodent studies indicates that AMPK activation promotes anti‐inflammatory responses in microglia exposed to danger signals or various stressors mainly through inhibition of the nuclear factor κB (NF‐κB) signaling and activation of the nuclear factor erythroid‐2‐related factor‐2 (Nrf2) pathway. However, AMPK activation in neurons exposed to stressors/insults may exacerbate neuronal damage if AMPK activation is excessive or prolonged. While AMPK affects microglial activation states and neuronal cell survival rates in both the adult and the developing brain, studies in the developing brain are still scarce, even though activated AMPK is highly expressed especially in the neonatal brain. More in depth studies in the developing brain are important, because neuroinflammation/neurodegeneration occurred during development can result in long‐lasting brain damage.

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Pattern recognition receptors mediate pro-inflammatory effects of extracellular mitochondrial transcription factor A (TFAM)

Cited by 34 publications

References 54 publications

The role of RAGE in host pathology and crosstalk between RAGE and TLR4 in innate immune signal transduction pathways

The role of RAGE in host pathology and crosstalk between RAGE and TLR4 in innate immune signal transduction pathways

Emerging perspectives on mitochondrial dysfunction and inflammation in Alzheimer’s disease

Involvement of AMP‐activated protein kinase in neuroinflammation and neurodegeneration in the adult and developing brain

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