Systems biology approaches to toll‐like receptor signaling

Vandenbon, Alexis; Teraguchi, Shunsuke; Akira, Shizuo; Takeda, Kiyoshi; Standley, Daron M.

doi:10.1002/wsbm.1178

Cited by 21 publications

(19 citation statements)

References 65 publications

(101 reference statements)

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“…Various systems biology approaches have been used to improve our understanding of TLR-mediated innate immune responses (14). However, an accurate and validated mathematical model of TLR signaling networks, with consideration of the dynamic crosstalk between various TLR pathways, has been hitherto lacking (15, 19–22, 24, 55–60).…”

Section: Discussionmentioning

confidence: 99%

“…Previous efforts that used systematic approaches to study TLR signaling (14) made it possible to construct a comprehensive map of the TLR signaling network from existing data in the literature (15); however, this provided a static visualization of the protein-protein interaction network implicated in TLR signaling. To assess the dynamics of this network, the TLR map has been reformulated to enable a steady state–based flux balance analysis (16).…”

Section: Introductionmentioning

confidence: 99%

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Innate immune memory and homeostasis may be conferred through crosstalk between the TLR3 and TLR7 pathways

Liu

Yang

et al. 2016

Sci. Signal.

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Toll-like receptors (TLRs) recognize pathogen-associated molecular patterns (PAMPs) and stimulate the innate immune response through the production of cytokines. The innate immune response depends on the timing of encountering PAMPs, suggesting a short-term “memory.” In particular, activation of TLR3 appears to prime macrophages for the subsequent activation of TLR7, which leads to synergistically increased production of cytokines. By developing a calibrated mathematical model for the kinetics of TLR3 and TLR7 pathway crosstalk and providing experimental validation, we demonstrated the involvement of the Janus-activated kinase (JAK)–signal transducer and activator of transcription (STAT) pathway in controlling the synergistic production of cytokines. Signaling through this pathway played a dual role: It mediated the synergistic production of cytokines, thus boosting the immune response, and it also maintained homeostasis to avoid an excessive inflammatory response. Thus, we propose that the JAK-STAT pathway provides a cytokine rheostat mechanism, which enables macrophages to fine-tune their responses to multiple, temporally separated infection events involving the TLR3 and TLR7 pathways.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Innate immune memory and homeostasis may be conferred through crosstalk between the TLR3 and TLR7 pathways

Liu

Yang

et al. 2016

Sci. Signal.

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“…The importance of lipid A recognition is evident by the widespread expression of the endotoxin receptor complex on macrophages, neutrophils, dendritic cells, mast cells, endothelial cells and natural killer cells as well as several populations of parenchymal cells (6, 7). Cells recognize lipid A via a surface receptor complex that is composed of the proteins myeloid differentiation factor 2 (MD2) and toll-like receptor 4 (TLR4) (8, 9) (Figure 2).…”

Section: Lipopolysaccharide Recognition and Signalingmentioning

confidence: 99%

The Immunobiology of Toll-Like Receptor 4 Agonists

Bohannon¹,

Hernandez²,

Enkhbaatar

et al. 2013

Shock

117

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Lipopolysaccharide (LPS, endotoxin) is a structural component of the Gram negative outer membrane. The lipid A moiety of LPS binds to the LPS receptor complex expressed by leukocytes, endothelial cells and parenchymal cells and is the primary component of Gram negative bacteria that is recognized by the immune system. Activation of the LPS receptor complex by native lipid A induces robust cytokine production, leukocyte activation and inflammation, which is beneficial for clearing bacterial infections at the local level but can cause severe systemic inflammation and shock at higher challenge doses. Interestingly, prior exposure to LPS renders the host resistant to shock caused by subsequent LPS challenge, a phenomenon known as endotoxin tolerance. Treatment with lipid A has also been shown to augment the host response to infection and to serve as a potent vaccine adjuvant. However, the side effects associated with the pronounced inflammatory response limits the use of native lipid A as a clinical immunomodulator. More recently, analogs of lipid A have been developed that possess attenuated pro-inflammatory activity but retain attractive immunomodulatory properties. The lipid A analog monophosphoryl lipid A (MPLA) exhibits approximately 1/1000th of the toxicity of native lipid A but retains potent immunoadjuvant activity. As such, MPLA is currently employed as an adjuvant in several human vaccine preparations. Due to the potency of lipid A analogs as immunoadjuvants, numerous laboratories are actively working to identify and develop new lipid A mimetics and to optimize their efficacy and safety. Based on those characteristics, lipid A analogs represent an attractive family of immunomodulators.

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“…The key to such therapies will be specificity to the receptor, the specific downstream signaling cascade(s), and the inflammatory mediators that are modulated by such therapies. Proceeding from models of TLR4 signaling of various degrees of complexity and model-derived insights on the ultimate roles of IL-1 in inflammation as applied to individual subjects, such computational models, would need to integrate the ever-increasing data on inflammasome biology [44], [45], [46], [47], [48] and [49]. We would envision a likely need for modulating different aspects of the intersecting TLR-NLR pathways with fine specificity, in a disease- (and possibly individual-) specific fashion.…”

Section: Introductionmentioning

confidence: 99%

Therapeutic strategies in inflammasome mediated diseases of the liver

Hoque

Vodovotz

Mehal

2013

Journal of Hepatology

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Summary Tissue stress and cell death result in inflammation even in the absence of pathogens. Such sterile inflammation is dependent on a cytosolic complex of proteins inside immune cells termed the inflammasome. This complex converts two groups of extracellular signals into an inflammatory response via activation of caspase-1 and secretion of IL-1β and IL-18. Group 1 signals are typically TOLL like receptor agonists and result in transcriptional upregulation of inflammasome components and pro-cytokines. Group 2 signals are diverse, ranging from uric acid to ATP, and lead to assembly and activation of the inflammasome complex. Inflammasome components are required for a wide range of acute and chronic pathologies, including experimental alcoholic and non-alcoholic steatohepatitis, and drug-induced liver injury. Collectively, group 1 and 2 signals, inflammasome components, and cytokine receptors provide a rich source of therapeutic targets. Many of the advances in the field have come from standard reductionist experiments. Progress in the understanding of complex human systems will, however, be dependent on novel strategies such as systems analysis, which analyze large data sets to provide new insights.

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Systems biology approaches to toll‐like receptor signaling

Cited by 21 publications

References 65 publications

Innate immune memory and homeostasis may be conferred through crosstalk between the TLR3 and TLR7 pathways

Innate immune memory and homeostasis may be conferred through crosstalk between the TLR3 and TLR7 pathways

The Immunobiology of Toll-Like Receptor 4 Agonists

Therapeutic strategies in inflammasome mediated diseases of the liver

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