NF-κB signaling in inflammation
14 Jul 2017-Signal Transduction and Targeted Therapy (Nature Publishing Group)-Vol. 2, Iss: 1, pp 17023
TL;DR: This review will discuss the activation and function of NF-κB in association with inflammatory diseases and highlight the development of therapeutic strategies based on NF-σB inhibition.
Abstract: The transcription factor NF-κB regulates multiple aspects of innate and adaptive immune functions and serves as a pivotal mediator of inflammatory responses. NF-κB induces the expression of various pro-inflammatory genes, including those encoding cytokines and chemokines, and also participates in inflammasome regulation. In addition, NF-κB plays a critical role in regulating the survival, activation and differentiation of innate immune cells and inflammatory T cells. Consequently, deregulated NF-κB activation contributes to the pathogenic processes of various inflammatory diseases. In this review, we will discuss the activation and function of NF-κB in association with inflammatory diseases and highlight the development of therapeutic strategies based on NF-κB inhibition.
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TL;DR: The authors explore the recent advancements in the field of metastasis and highlight the latest insights that contribute to shaping this hallmark of cancer.
Abstract: Metastasis is the hallmark of cancer that is responsible for the greatest number of cancer-related deaths. Yet, it remains poorly understood. The continuous evolution of cancer biology research and the emergence of new paradigms in the study of metastasis have revealed some of the molecular underpinnings of this dissemination process. The invading tumor cell, on its way to the target site, interacts with other proteins and cells. Recognition of these interactions improved the understanding of some of the biological principles of the metastatic cell that govern its mobility and plasticity. Communication with the tumor microenvironment allows invading cancer cells to overcome stromal challenges, settle, and colonize. These characteristics of cancer cells are driven by genetic and epigenetic modifications within the tumor cell itself and its microenvironment. Establishing the biological mechanisms of the metastatic process is crucial in finding open therapeutic windows for successful interventions. In this review, the authors explore the recent advancements in the field of metastasis and highlight the latest insights that contribute to shaping this hallmark of cancer.
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TL;DR: It is suggested that blocking the cytokine-mediated inflammatory cell death signaling pathway identified here may benefit patients with COVID-19 or other infectious and autoinflammatory diseases by limiting tissue damage/inflammation.
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TL;DR: Biochemical, structural and functional studies on the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) papain-like protease PLpro reveal that it regulates host antiviral responses by preferentially cleaving the ubiquitin-like interferon-stimulated gene 15 protein (ISG15) and identify this protease as a potential therapeutic target for coronav virus disease 2019 (COVID-19).
Abstract: The papain-like protease PLpro is an essential coronavirus enzyme that is required for processing viral polyproteins to generate a functional replicase complex and enable viral spread1,2. PLpro is also implicated in cleaving proteinaceous post-translational modifications on host proteins as an evasion mechanism against host antiviral immune responses3-5. Here we perform biochemical, structural and functional characterization of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) PLpro (SCoV2-PLpro) and outline differences with SARS-CoV PLpro (SCoV-PLpro) in regulation of host interferon and NF-κB pathways. SCoV2-PLpro and SCoV-PLpro share 83% sequence identity but exhibit different host substrate preferences; SCoV2-PLpro preferentially cleaves the ubiquitin-like interferon-stimulated gene 15 protein (ISG15), whereas SCoV-PLpro predominantly targets ubiquitin chains. The crystal structure of SCoV2-PLpro in complex with ISG15 reveals distinctive interactions with the amino-terminal ubiquitin-like domain of ISG15, highlighting the high affinity and specificity of these interactions. Furthermore, upon infection, SCoV2-PLpro contributes to the cleavage of ISG15 from interferon responsive factor 3 (IRF3) and attenuates type I interferon responses. Notably, inhibition of SCoV2-PLpro with GRL-0617 impairs the virus-induced cytopathogenic effect, maintains the antiviral interferon pathway and reduces viral replication in infected cells. These results highlight a potential dual therapeutic strategy in which targeting of SCoV2-PLpro can suppress SARS-CoV-2 infection and promote antiviral immunity.
729 citations
TL;DR: This review attempts to summarize the current knowledge and updates on the mechanisms of NF-κB pathway regulation and the potential therapeutic application of inhibition of NF -κB signaling in cancer and inflammatory diseases.
Abstract: NF-κB pathway consists of canonical and non-canonical pathways. The canonical NF-κB is activated by various stimuli, transducing a quick but transient transcriptional activity, to regulate the expression of various proinflammatory genes and also serve as the critical mediator for inflammatory response. Meanwhile, the activation of the non-canonical NF-κB pathway occurs through a handful of TNF receptor superfamily members. Since the activation of this pathway involves protein synthesis, the kinetics of non-canonical NF-κB activation is slow but persistent, in concordance with its biological functions in the development of immune cell and lymphoid organ, immune homeostasis and immune response. The activation of the canonical and non-canonical NF-κB pathway is tightly controlled, highlighting the vital roles of ubiquitination in these pathways. Emerging studies indicate that dysregulated NF-κB activity causes inflammation-related diseases as well as cancers, and NF-κB has been long proposed as the potential target for therapy of diseases. This review attempts to summarize our current knowledge and updates on the mechanisms of NF-κB pathway regulation and the potential therapeutic application of inhibition of NF-κB signaling in cancer and inflammatory diseases.
408 citations
TL;DR: This review of recent research on the dynamics of NF-κB signaling focuses on how these dynamics vary in different cell types, while discussing why these characteristics may be important and how new techniques and technologies should allow for appropriate control of innate immune responses.
Abstract: The nuclear factor-κB (NF-κB) signaling pathway is one of the best understood immune-related pathways thanks to almost four decades of intense research. NF-κB signaling is activated by numerous discrete stimuli and is a master regulator of the inflammatory response to pathogens and cancerous cells, as well as a key regulator of autoimmune diseases. In this regard, the role of NF-κB signaling in immunity is not unlike that of the macrophage. The dynamics by which NF-κB proteins shuttle between the cytoplasm and the nucleus to initiate transcription have been studied rigorously in fibroblasts and other non-hematopoietic cells, but many questions remain as to how current models of NF-κB signaling and dynamics can be translated to innate immune cells such as macrophages. In this review, we will present recent research on the dynamics of NF-κB signaling and focus especially on how these dynamics vary in different cell types, while discussing why these characteristics may be important. We will end by looking ahead to how new techniques and technologies should allow us to analyze these signaling processes with greater clarity, bringing us closer to a more complete understanding of inflammatory transcription factor dynamics and how different cellular contexts might allow for appropriate control of innate immune responses.
395 citations
Cites background from "NF-κB signaling in inflammation"
...This synergy only occurred when combining TLR ligands in such a way that both MyD88 and TRIF were utilized (i.e., triggering one TLR that signals through each adaptor), again showing that connecting these two pathways leads to enhanced inflammatory gene transcription likely by activating multiple transcription factor classes....
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...(4) Subsequently, the pathogen is brought into a sub-cellular compartment where it is sensed by an alternate PRR (or, in the case of TLR4, the same PRR but in a new sub-cellular context) which signals through a second adaptor TRIF (5), leading to the activation of more NF-κB dimers as well as other transcription factors, such as IRF3, leading to type I IFN production, and AP-1, which is activated via the MAPK pathway....
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...For example, triggering the TRIF-IRF3IFN pathway leads to the release of type I IFNs, which will then bind to the type I IFN receptor (IFNAR) on the surface of the same cell (32), modulating signaling events that are still happening due to the original response to LPS or other cytokines (33)....
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...which signals through a second adaptor TRIF (5), leading to the activation of more NF-κB dimers as well as other transcription factors, such as IRF3, leading to type I...
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...(7) It should be noted that, while both MyD88 and TRIF are known to activate MAPKs, it remains unclear what their relative contributions are in regard to AP-1 activation and TNF production in the context of LPS stimulation. higher ligand doses (41, 50, 64)....
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References
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TL;DR: Recent advances that have been made by research into the role of TLR biology in host defense and disease are described.
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TL;DR: The role of PRRs, their signaling pathways, and how they control inflammatory responses are discussed.
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TL;DR: The identification of mechanisms and molecules associated with macrophage plasticity and polarized activation provides a basis for Macrophage-centered diagnostic and therapeutic strategies.
Abstract: Diversity and plasticity are hallmarks of cells of the monocyte-macrophage lineage. In response to IFNs, Toll-like receptor engagement, or IL-4/IL-13 signaling, macrophages undergo M1 (classical) or M2 (alternative) activation, which represent extremes of a continuum in a universe of activation states. Progress has now been made in defining the signaling pathways, transcriptional networks, and epigenetic mechanisms underlying M1-M2 or M2-like polarized activation. Functional skewing of mononuclear phagocytes occurs in vivo under physiological conditions (e.g., ontogenesis and pregnancy) and in pathology (allergic and chronic inflammation, tissue repair, infection, and cancer). However, in selected preclinical and clinical conditions, coexistence of cells in different activation states and unique or mixed phenotypes have been observed, a reflection of dynamic changes and complex tissue-derived signals. The identification of mechanisms and molecules associated with macrophage plasticity and polarized activation provides a basis for macrophage-centered diagnostic and therapeutic strategies.
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TL;DR: The authors synthesize some of the basic principles that have emerged from studies of NF-kappaB, and aim to generate a more unified view of the regulation of the transcription factor.
3,996 citations
TL;DR: It is shown that mitophagy/autophagy blockade leads to the accumulation of damaged, ROS-generating mitochondria, and this in turn activates the NLRP3 inflammasome, and may explain the frequent association of mitochondrial damage with inflammatory diseases.
Abstract: An inflammatory response initiated by the NLRP3 inflammasome is triggered by a variety of situations of host 'danger', including infection and metabolic dysregulation. Previous studies suggested that NLRP3 inflammasome activity is negatively regulated by autophagy and positively regulated by reactive oxygen species (ROS) derived from an uncharacterized organelle. Here we show that mitophagy/autophagy blockade leads to the accumulation of damaged, ROS-generating mitochondria, and this in turn activates the NLRP3 inflammasome. Resting NLRP3 localizes to endoplasmic reticulum structures, whereas on inflammasome activation both NLRP3 and its adaptor ASC redistribute to the perinuclear space where they co-localize with endoplasmic reticulum and mitochondria organelle clusters. Notably, both ROS generation and inflammasome activation are suppressed when mitochondrial activity is dysregulated by inhibition of the voltage-dependent anion channel. This indicates that NLRP3 inflammasome senses mitochondrial dysfunction and may explain the frequent association of mitochondrial damage with inflammatory diseases.
3,985 citations